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1.  Mouse models address key concerns regarding autophagy inhibition in cancer therapy 
Cancer discovery  2014;4(8):873-875.
Summary
With multiple clinical trials underway targeting autophagy against cancer, Yang et al. (1) and Karsli-Uzunbas et al. (2) address important concerns regarding autophagy inhibition in cancer patients using genetically engineered mouse models (GEMMs) that more accurately represent the tumor biology found in human pancreatic and lung cancer patients.
doi:10.1158/2159-8290.CD-14-0618
PMCID: PMC4124512  PMID: 25092744
2.  Autophagy dependent production of secreted factors facilitates oncogenic RAS-driven invasion 
Cancer discovery  2014;4(4):466-479.
The tumor promoting functions of autophagy are primarily attributed to its ability to promote cancer cell survival. However, emerging evidence suggests that autophagy plays other roles during tumorigenesis. Here, we uncover that autophagy promotes oncogenic RAS-driven invasion. In epithelial cells transformed with oncogenic RAS, depletion of autophagy-related genes suppresses invasion in three-dimensional culture, decreases cell motility, and reduces pulmonary metastases in vivo. Treatment with conditioned media from autophagy-competent cells rescues the invasive capacity of autophagy-deficient cells, indicating these cells fail to secrete factors required for RAS-driven invasion. Reduced autophagy diminishes the secretion of the pro-migratory cytokine IL6, which is necessary to restore invasion of autophagy-deficient cells. Moreover, autophagy-deficient cells exhibit reduced levels of MMP2 and WNT5A. These results support a previously unrecognized function for autophagy in promoting cancer cell invasion via the coordinate production of multiple secreted factors.
doi:10.1158/2159-8290.CD-13-0841
PMCID: PMC3980002  PMID: 24513958
Autophagy; RAS; Invasion; Three-dimensional culture; Secretion; Interleukin 6
3.  Aetiological Profile and Antibiotic Susceptibility Pattern in Patients with Urinary Tract Infection in Tripura 
doi:10.7860/JCDR/2014/8711.4681
PMCID: PMC4190717  PMID: 25302196
Antibiotic susceptibility; Empirical; Urinary tract infection
4.  IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway 
Autophagy  2013;9(8):1214-1227.
Adherent cells require proper integrin-mediated extracellular matrix (ECM) engagement for growth and survival; normal cells deprived of proper ECM contact undergo anoikis. At the same time, autophagy is induced as a survival pathway in both fibroblasts and epithelial cells upon ECM detachment. Here, we further define the intracellular signals that mediate detachment-induced autophagy and uncover an important role for the IκB kinase (IKK) complex in the induction of autophagy in mammary epithelial cells (MECs) deprived of ECM contact. Whereas the PI3K-AKT-MTORC1 pathway activation potently inhibits autophagy in ECM-detached fibroblasts, enforced activation of this pathway is not sufficient to suppress detachment-induced autophagy in MECs. Instead, inhibition of IKK, as well as its upstream regulator, MAP3K7/TAK1, significantly attenuates detachment-induced autophagy in MECs. Furthermore, function-blocking experiments corroborate that both IKK activation and autophagy induction result from decreased ITGA3-ITGB1 (α3β1 integrin) function. Finally, we demonstrate that pharmacological IKK inhibition enhances anoikis and accelerates luminal apoptosis during acinar morphogenesis in three-dimensional culture. Based on these results, we propose that the IKK complex functions as a key mediator of detachment-induced autophagy and anoikis resistance in epithelial cells.
doi:10.4161/auto.24870
PMCID: PMC3748193  PMID: 23778976
autophagy; anoikis; extracellular matrix; integrin; mammary epithelial cells
5.  Autophagy As A Stress Response And Quality Control Mechanism—Implications for Cell Injury and Human Disease 
Annual review of pathology  2012;8:105-137.
Autophagy, a vital catabolic process that degrades cytoplasmic components within the lysosome, serves as an essential cytoprotective response to pathologic stresses that occur during diseases such as cancer, ischemia, and infection. In addition to its role as a stress response pathway, autophagy plays an essential quality control function in the cell by promoting basal turnover of long-lived proteins and organelles as well as selectively degrading damaged cellular components. This homeostatic function protects against a wide variety of diseases including neurodegeneration, myopathy, liver disease, and diabetes. This review discusses our current understanding of these two principal functions for autophagy as a physiologic stress response and quality control mechanism within mammalian cells and details how alterations in autophagy promote human disease.
doi:10.1146/annurev-pathol-020712-163918
PMCID: PMC3971121  PMID: 23072311
Macroautophagy; lysosome; mitophagy; inflammation; neurodegeneration; myopathy
6.  Autophagy Restricts Proliferation Driven By Oncogenic Phosphatidylinositol 3-Kinase in Three-Dimensional Culture 
Oncogene  2012;32(20):2543-2554.
Autophagy is a tightly regulated lysosomal self-digestion process that can both promote and impede tumorigenesis. Here, we utilize a three-dimensional (3D) culture model to address how interactions between autophagy and the PI3K/Akt/mTOR pathway impact the malignant behavior of cells carrying a tumor-derived, activating mutation in PI3K (PI3K-H1047R). In this model, autophagy simultaneously mediates tumor suppressive and promoting functions within individual glandular structures. In 3D culture, constitutive PI3K activation overcomes proliferation arrest and promotes resistance to anoikis in the luminal space, resulting in aberrant structures with filled lumen. Inhibiting autophagy in PI3K-H1047R structures triggers luminal cell apoptosis, resulting in lumen clearance. At the same time, ATG depletion strongly enhances PI3K-H1047R cell proliferation during 3D morphogenesis, revealing an unexpected role for autophagy in restricting proliferation driven by PI3K activation. Intriguingly, over-expression of the autophagy cargo receptor p62/SQSTM1 in PI3K-H1047R cells is sufficient to enhance cell proliferation, activate the ERK/MAPK pathway, and to promote EGF-independent proliferation in 3D culture. Overall, these results indicate that autophagy antagonizes specific aspects of oncogenic PI3K transformation, with the loss of autophagy promoting proliferation.
doi:10.1038/onc.2012.277
PMCID: PMC3470740  PMID: 22777351
Autophagy; oncogenic PI3K; proliferation; 3D culture
7.  FoxO3a Directs a Protective Autophagy Program in Hematopoietic Stem Cells 
Nature  2013;494(7437):323-327.
Blood production is ensured by rare self-renewing hematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here, we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy following ex vivo cytokine withdrawal and in vivo caloric restriction. We demonstrate that FoxO3a is critical to maintain a gene expression program that poise HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FoxO3a-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.
doi:10.1038/nature11895
PMCID: PMC3579002  PMID: 23389440
8.  Regulation of Tumor Cell Dormancy by Tissue Microenvironments and Autophagy 
The development of metastasis is the major cause of death in cancer patients. In certain instances, this occurs shortly after primary tumor detection and treatment, indicating these lesions were already expanding at the moment of diagnosis or initiated exponential growth shortly after. However, in many types of cancer, patients succumb to metastatic disease years and sometimes decades after being treated for a primary tumor. This has led to the notion that in these patients residual disease may remain in a dormant state. Tumor cell dormancy is a poorly understood phase of cancer progression and only recently have its underlying molecular mechanisms started to be revealed. Important questions that remain to be elucidated include not only which mechanisms prevent residual disease from proliferating but also which mechanisms critically maintain the long-term survival of these disseminated residual cells. Herein, we review recent evidence in support of genetic and epigenetic mechanisms driving dormancy. We also explore how therapy may cause the onset of dormancy in the surviving fraction of cells after treatment and how autophagy may be a mechanism that maintains the residual cells that are viable for prolonged periods.
doi:10.1007/978-1-4614-1445-2_5
PMCID: PMC3651695  PMID: 23143976
Quiescence; Minimal residual disease; Cellular stress; p38; MAPK; Metastasis
9.  Guidelines for the use and interpretation of assays for monitoring autophagy 
Klionsky, Daniel J. | Abdalla, Fabio C. | Abeliovich, Hagai | Abraham, Robert T. | Acevedo-Arozena, Abraham | Adeli, Khosrow | Agholme, Lotta | Agnello, Maria | Agostinis, Patrizia | Aguirre-Ghiso, Julio A. | Ahn, Hyung Jun | Ait-Mohamed, Ouardia | Ait-Si-Ali, Slimane | Akematsu, Takahiko | Akira, Shizuo | Al-Younes, Hesham M. | Al-Zeer, Munir A. | Albert, Matthew L. | Albin, Roger L. | Alegre-Abarrategui, Javier | Aleo, Maria Francesca | Alirezaei, Mehrdad | Almasan, Alexandru | Almonte-Becerril, Maylin | Amano, Atsuo | Amaravadi, Ravi K. | Amarnath, Shoba | Amer, Amal O. | Andrieu-Abadie, Nathalie | Anantharam, Vellareddy | Ann, David K. | Anoopkumar-Dukie, Shailendra | Aoki, Hiroshi | Apostolova, Nadezda | Arancia, Giuseppe | Aris, John P. | Asanuma, Katsuhiko | Asare, Nana Y.O. | Ashida, Hisashi | Askanas, Valerie | Askew, David S. | Auberger, Patrick | Baba, Misuzu | Backues, Steven K. | Baehrecke, Eric H. | Bahr, Ben A. | Bai, Xue-Yuan | Bailly, Yannick | Baiocchi, Robert | Baldini, Giulia | Balduini, Walter | Ballabio, Andrea | Bamber, Bruce A. | Bampton, Edward T.W. | Juhász, Gábor | Bartholomew, Clinton R. | Bassham, Diane C. | Bast, Robert C. | Batoko, Henri | Bay, Boon-Huat | Beau, Isabelle | Béchet, Daniel M. | Begley, Thomas J. | Behl, Christian | Behrends, Christian | Bekri, Soumeya | Bellaire, Bryan | Bendall, Linda J. | Benetti, Luca | Berliocchi, Laura | Bernardi, Henri | Bernassola, Francesca | Besteiro, Sébastien | Bhatia-Kissova, Ingrid | Bi, Xiaoning | Biard-Piechaczyk, Martine | Blum, Janice S. | Boise, Lawrence H. | Bonaldo, Paolo | Boone, David L. | Bornhauser, Beat C. | Bortoluci, Karina R. | Bossis, Ioannis | Bost, Frédéric | Bourquin, Jean-Pierre | Boya, Patricia | Boyer-Guittaut, Michaël | Bozhkov, Peter V. | Brady, Nathan R | Brancolini, Claudio | Brech, Andreas | Brenman, Jay E. | Brennand, Ana | Bresnick, Emery H. | Brest, Patrick | Bridges, Dave | Bristol, Molly L. | Brookes, Paul S. | Brown, Eric J. | Brumell, John H. | Brunetti-Pierri, Nicola | Brunk, Ulf T. | Bulman, Dennis E. | Bultman, Scott J. | Bultynck, Geert | Burbulla, Lena F. | Bursch, Wilfried | Butchar, Jonathan P. | Buzgariu, Wanda | Bydlowski, Sergio P. | Cadwell, Ken | Cahová, Monika | Cai, Dongsheng | Cai, Jiyang | Cai, Qian | Calabretta, Bruno | Calvo-Garrido, Javier | Camougrand, Nadine | Campanella, Michelangelo | Campos-Salinas, Jenny | Candi, Eleonora | Cao, Lizhi | Caplan, Allan B. | Carding, Simon R. | Cardoso, Sandra M. | Carew, Jennifer S. | Carlin, Cathleen R. | Carmignac, Virginie | Carneiro, Leticia A.M. | Carra, Serena | Caruso, Rosario A. | Casari, Giorgio | Casas, Caty | Castino, Roberta | Cebollero, Eduardo | Cecconi, Francesco | Celli, Jean | Chaachouay, Hassan | Chae, Han-Jung | Chai, Chee-Yin | Chan, David C. | Chan, Edmond Y. | Chang, Raymond Chuen-Chung | Che, Chi-Ming | Chen, Ching-Chow | Chen, Guang-Chao | Chen, Guo-Qiang | Chen, Min | Chen, Quan | Chen, Steve S.-L. | Chen, WenLi | Chen, Xi | Chen, Xiangmei | Chen, Xiequn | Chen, Ye-Guang | Chen, Yingyu | Chen, Yongqiang | Chen, Yu-Jen | Chen, Zhixiang | Cheng, Alan | Cheng, Christopher H.K. | Cheng, Yan | Cheong, Heesun | Cheong, Jae-Ho | Cherry, Sara | Chess-Williams, Russ | Cheung, Zelda H. | Chevet, Eric | Chiang, Hui-Ling | Chiarelli, Roberto | Chiba, Tomoki | Chin, Lih-Shen | Chiou, Shih-Hwa | Chisari, Francis V. | Cho, Chi Hin | Cho, Dong-Hyung | Choi, Augustine M.K. | Choi, DooSeok | Choi, Kyeong Sook | Choi, Mary E. | Chouaib, Salem | Choubey, Divaker | Choubey, Vinay | Chu, Charleen T. | Chuang, Tsung-Hsien | Chueh, Sheau-Huei | Chun, Taehoon | Chwae, Yong-Joon | Chye, Mee-Len | Ciarcia, Roberto | Ciriolo, Maria R. | Clague, Michael J. | Clark, Robert S.B. | Clarke, Peter G.H. | Clarke, Robert | Codogno, Patrice | Coller, Hilary A. | Colombo, María I. | Comincini, Sergio | Condello, Maria | Condorelli, Fabrizio | Cookson, Mark R. | Coombs, Graham H. | Coppens, Isabelle | Corbalan, Ramon | Cossart, Pascale | Costelli, Paola | Costes, Safia | Coto-Montes, Ana | Couve, Eduardo | Coxon, Fraser P. | Cregg, James M. | Crespo, José L. | Cronjé, Marianne J. | Cuervo, Ana Maria | Cullen, Joseph J. | Czaja, Mark J. | D'Amelio, Marcello | Darfeuille-Michaud, Arlette | Davids, Lester M. | Davies, Faith E. | De Felici, Massimo | de Groot, John F. | de Haan, Cornelis A.M. | De Martino, Luisa | De Milito, Angelo | De Tata, Vincenzo | Debnath, Jayanta | Degterev, Alexei | Dehay, Benjamin | Delbridge, Lea M.D. | Demarchi, Francesca | Deng, Yi Zhen | Dengjel, Jörn | Dent, Paul | Denton, Donna | Deretic, Vojo | Desai, Shyamal D. | Devenish, Rodney J. | Di Gioacchino, Mario | Di Paolo, Gilbert | Di Pietro, Chiara | Díaz-Araya, Guillermo | Díaz-Laviada, Inés | Diaz-Meco, Maria T. | Diaz-Nido, Javier | Dikic, Ivan | Dinesh-Kumar, Savithramma P. | Ding, Wen-Xing | Distelhorst, Clark W. | Diwan, Abhinav | Djavaheri-Mergny, Mojgan | Dokudovskaya, Svetlana | Dong, Zheng | Dorsey, Frank C. | Dosenko, Victor | Dowling, James J. | Doxsey, Stephen | Dreux, Marlène | Drew, Mark E. | Duan, Qiuhong | Duchosal, Michel A. | Duff, Karen E. | Dugail, Isabelle | Durbeej, Madeleine | Duszenko, Michael | Edelstein, Charles L. | Edinger, Aimee L. | Egea, Gustavo | Eichinger, Ludwig | Eissa, N. Tony | Ekmekcioglu, Suhendan | El-Deiry, Wafik S. | Elazar, Zvulun | Elgendy, Mohamed | Ellerby, Lisa M. | Eng, Kai Er | Engelbrecht, Anna-Mart | Engelender, Simone | Erenpreisa, Jekaterina | Escalante, Ricardo | Esclatine, Audrey | Eskelinen, Eeva-Liisa | Espert, Lucile | Espina, Virginia | Fan, Huizhou | Fan, Jia | Fan, Qi-Wen | Fan, Zhen | Fang, Shengyun | Fang, Yongqi | Fanto, Manolis | Fanzani, Alessandro | Farkas, Thomas | Farre, Jean-Claude | Faure, Mathias | Fechheimer, Marcus | Feng, Carl G. | Feng, Jian | Feng, Qili | Feng, Youji | Fésüs, László | Feuer, Ralph | Figueiredo-Pereira, Maria E. | Fimia, Gian Maria | Fingar, Diane C. | Finkbeiner, Steven | Finkel, Toren | Finley, Kim D. | Fiorito, Filomena | Fisher, Edward A. | Fisher, Paul B. | Flajolet, Marc | Florez-McClure, Maria L. | Florio, Salvatore | Fon, Edward A. | Fornai, Francesco | Fortunato, Franco | Fotedar, Rati | Fowler, Daniel H. | Fox, Howard S. | Franco, Rodrigo | Frankel, Lisa B. | Fransen, Marc | Fuentes, José M. | Fueyo, Juan | Fujii, Jun | Fujisaki, Kozo | Fujita, Eriko | Fukuda, Mitsunori | Furukawa, Ruth H. | Gaestel, Matthias | Gailly, Philippe | Gajewska, Malgorzata | Galliot, Brigitte | Galy, Vincent | Ganesh, Subramaniam | Ganetzky, Barry | Ganley, Ian G. | Gao, Fen-Biao | Gao, George F. | Gao, Jinming | Garcia, Lorena | Garcia-Manero, Guillermo | Garcia-Marcos, Mikel | Garmyn, Marjan | Gartel, Andrei L. | Gatti, Evelina | Gautel, Mathias | Gawriluk, Thomas R. | Gegg, Matthew E. | Geng, Jiefei | Germain, Marc | Gestwicki, Jason E. | Gewirtz, David A. | Ghavami, Saeid | Ghosh, Pradipta | Giammarioli, Anna M. | Giatromanolaki, Alexandra N. | Gibson, Spencer B. | Gilkerson, Robert W. | Ginger, Michael L. | Ginsberg, Henry N. | Golab, Jakub | Goligorsky, Michael S. | Golstein, Pierre | Gomez-Manzano, Candelaria | Goncu, Ebru | Gongora, Céline | Gonzalez, Claudio D. | Gonzalez, Ramon | González-Estévez, Cristina | González-Polo, Rosa Ana | Gonzalez-Rey, Elena | Gorbunov, Nikolai V. | Gorski, Sharon | Goruppi, Sandro | Gottlieb, Roberta A. | Gozuacik, Devrim | Granato, Giovanna Elvira | Grant, Gary D. | Green, Kim N. | Gregorc, Ales | Gros, Frédéric | Grose, Charles | Grunt, Thomas W. | Gual, Philippe | Guan, Jun-Lin | Guan, Kun-Liang | Guichard, Sylvie M. | Gukovskaya, Anna S. | Gukovsky, Ilya | Gunst, Jan | Gustafsson, Åsa B. | Halayko, Andrew J. | Hale, Amber N. | Halonen, Sandra K. | Hamasaki, Maho | Han, Feng | Han, Ting | Hancock, Michael K. | Hansen, Malene | Harada, Hisashi | Harada, Masaru | Hardt, Stefan E. | Harper, J. Wade | Harris, Adrian L. | Harris, James | Harris, Steven D. | Hashimoto, Makoto | Haspel, Jeffrey A. | Hayashi, Shin-ichiro | Hazelhurst, Lori A. | He, Congcong | He, You-Wen | Hébert, Marie-Josée | Heidenreich, Kim A. | Helfrich, Miep H. | Helgason, Gudmundur V. | Henske, Elizabeth P. | Herman, Brian | Herman, Paul K. | Hetz, Claudio | Hilfiker, Sabine | Hill, Joseph A. | Hocking, Lynne J. | Hofman, Paul | Hofmann, Thomas G. | Höhfeld, Jörg | Holyoake, Tessa L. | Hong, Ming-Huang | Hood, David A. | Hotamisligil, Gökhan S. | Houwerzijl, Ewout J. | Høyer-Hansen, Maria | Hu, Bingren | Hu, Chien-an A. | Hu, Hong-Ming | Hua, Ya | Huang, Canhua | Huang, Ju | Huang, Shengbing | Huang, Wei-Pang | Huber, Tobias B. | Huh, Won-Ki | Hung, Tai-Ho | Hupp, Ted R. | Hur, Gang Min | Hurley, James B. | Hussain, Sabah N.A. | Hussey, Patrick J. | Hwang, Jung Jin | Hwang, Seungmin | Ichihara, Atsuhiro | Ilkhanizadeh, Shirin | Inoki, Ken | Into, Takeshi | Iovane, Valentina | Iovanna, Juan L. | Ip, Nancy Y. | Isaka, Yoshitaka | Ishida, Hiroyuki | Isidoro, Ciro | Isobe, Ken-ichi | Iwasaki, Akiko | Izquierdo, Marta | Izumi, Yotaro | Jaakkola, Panu M. | Jäättelä, Marja | Jackson, George R. | Jackson, William T. | Janji, Bassam | Jendrach, Marina | Jeon, Ju-Hong | Jeung, Eui-Bae | Jiang, Hong | Jiang, Hongchi | Jiang, Jean X. | Jiang, Ming | Jiang, Qing | Jiang, Xuejun | Jiang, Xuejun | Jiménez, Alberto | Jin, Meiyan | Jin, Shengkan V. | Joe, Cheol O. | Johansen, Terje | Johnson, Daniel E. | Johnson, Gail V.W. | Jones, Nicola L. | Joseph, Bertrand | Joseph, Suresh K. | Joubert, Annie M. | Juhász, Gábor | Juillerat-Jeanneret, Lucienne | Jung, Chang Hwa | Jung, Yong-Keun | Kaarniranta, Kai | Kaasik, Allen | Kabuta, Tomohiro | Kadowaki, Motoni | Kågedal, Katarina | Kamada, Yoshiaki | Kaminskyy, Vitaliy O. | Kampinga, Harm H. | Kanamori, Hiromitsu | Kang, Chanhee | Kang, Khong Bee | Kang, Kwang Il | Kang, Rui | Kang, Yoon-A | Kanki, Tomotake | Kanneganti, Thirumala-Devi | Kanno, Haruo | Kanthasamy, Anumantha G. | Kanthasamy, Arthi | Karantza, Vassiliki | Kaushal, Gur P. | Kaushik, Susmita | Kawazoe, Yoshinori | Ke, Po-Yuan | Kehrl, John H. | Kelekar, Ameeta | Kerkhoff, Claus | Kessel, David H. | Khalil, Hany | Kiel, Jan A.K.W. | Kiger, Amy A. | Kihara, Akio | Kim, Deok Ryong | Kim, Do-Hyung | Kim, Dong-Hou | Kim, Eun-Kyoung | Kim, Hyung-Ryong | Kim, Jae-Sung | Kim, Jeong Hun | Kim, Jin Cheon | Kim, John K. | Kim, Peter K. | Kim, Seong Who | Kim, Yong-Sun | Kim, Yonghyun | Kimchi, Adi | Kimmelman, Alec C. | King, Jason S. | Kinsella, Timothy J. | Kirkin, Vladimir | Kirshenbaum, Lorrie A. | Kitamoto, Katsuhiko | Kitazato, Kaio | Klein, Ludger | Klimecki, Walter T. | Klucken, Jochen | Knecht, Erwin | Ko, Ben C.B. | Koch, Jan C. | Koga, Hiroshi | Koh, Jae-Young | Koh, Young Ho | Koike, Masato | Komatsu, Masaaki | Kominami, Eiki | Kong, Hee Jeong | Kong, Wei-Jia | Korolchuk, Viktor I. | Kotake, Yaichiro | Koukourakis, Michael I. | Flores, Juan B. Kouri | Kovács, Attila L. | Kraft, Claudine | Krainc, Dimitri | Krämer, Helmut | Kretz-Remy, Carole | Krichevsky, Anna M. | Kroemer, Guido | Krüger, Rejko | Krut, Oleg | Ktistakis, Nicholas T. | Kuan, Chia-Yi | Kucharczyk, Roza | Kumar, Ashok | Kumar, Raj | Kumar, Sharad | Kundu, Mondira | Kung, Hsing-Jien | Kurz, Tino | Kwon, Ho Jeong | La Spada, Albert R. | Lafont, Frank | Lamark, Trond | Landry, Jacques | Lane, Jon D. | Lapaquette, Pierre | Laporte, Jocelyn F. | László, Lajos | Lavandero, Sergio | Lavoie, Josée N. | Layfield, Robert | Lazo, Pedro A. | Le, Weidong | Le Cam, Laurent | Ledbetter, Daniel J. | Lee, Alvin J.X. | Lee, Byung-Wan | Lee, Gyun Min | Lee, Jongdae | lee, Ju-hyun | Lee, Michael | Lee, Myung-Shik | Lee, Sug Hyung | Leeuwenburgh, Christiaan | Legembre, Patrick | Legouis, Renaud | Lehmann, Michael | Lei, Huan-Yao | Lei, Qun-Ying | Leib, David A. | Leiro, José | Lemasters, John J. | Lemoine, Antoinette | Lesniak, Maciej S. | Lev, Dina | Levenson, Victor V. | Levine, Beth | Levy, Efrat | Li, Faqiang | Li, Jun-Lin | Li, Lian | Li, Sheng | Li, Weijie | Li, Xue-Jun | Li, Yan-Bo | Li, Yi-Ping | Liang, Chengyu | Liang, Qiangrong | Liao, Yung-Feng | Liberski, Pawel P. | Lieberman, Andrew | Lim, Hyunjung J. | Lim, Kah-Leong | Lim, Kyu | Lin, Chiou-Feng | Lin, Fu-Cheng | Lin, Jian | Lin, Jiandie D. | Lin, Kui | Lin, Wan-Wan | Lin, Weei-Chin | Lin, Yi-Ling | Linden, Rafael | Lingor, Paul | Lippincott-Schwartz, Jennifer | Lisanti, Michael P. | Liton, Paloma B. | Liu, Bo | Liu, Chun-Feng | Liu, Kaiyu | Liu, Leyuan | Liu, Qiong A. | Liu, Wei | Liu, Young-Chau | Liu, Yule | Lockshin, Richard A. | Lok, Chun-Nam | Lonial, Sagar | Loos, Benjamin | Lopez-Berestein, Gabriel | López-Otín, Carlos | Lossi, Laura | Lotze, Michael T. | Low, Peter | Lu, Binfeng | Lu, Bingwei | Lu, Bo | Lu, Zhen | Luciano, Fréderic | Lukacs, Nicholas W. | Lund, Anders H. | Lynch-Day, Melinda A. | Ma, Yong | Macian, Fernando | MacKeigan, Jeff P. | Macleod, Kay F. | Madeo, Frank | Maiuri, Luigi | Maiuri, Maria Chiara | Malagoli, Davide | Malicdan, May Christine V. | Malorni, Walter | Man, Na | Mandelkow, Eva-Maria | Manon, Stephen | Manov, Irena | Mao, Kai | Mao, Xiang | Mao, Zixu | Marambaud, Philippe | Marazziti, Daniela | Marcel, Yves L. | Marchbank, Katie | Marchetti, Piero | Marciniak, Stefan J. | Marcondes, Mateus | Mardi, Mohsen | Marfe, Gabriella | Mariño, Guillermo | Markaki, Maria | Marten, Mark R. | Martin, Seamus J. | Martinand-Mari, Camille | Martinet, Wim | Martinez-Vicente, Marta | Masini, Matilde | Matarrese, Paola | Matsuo, Saburo | Matteoni, Raffaele | Mayer, Andreas | Mazure, Nathalie M. | McConkey, David J. | McConnell, Melanie J. | McDermott, Catherine | McDonald, Christine | McInerney, Gerald M. | McKenna, Sharon L. | McLaughlin, BethAnn | McLean, Pamela J. | McMaster, Christopher R. | McQuibban, G. Angus | Meijer, Alfred J. | Meisler, Miriam H. | Meléndez, Alicia | Melia, Thomas J. | Melino, Gerry | Mena, Maria A. | Menendez, Javier A. | Menna-Barreto, Rubem F. S. | Menon, Manoj B. | Menzies, Fiona M. | Mercer, Carol A. | Merighi, Adalberto | Merry, Diane E. | Meschini, Stefania | Meyer, Christian G. | Meyer, Thomas F. | Miao, Chao-Yu | Miao, Jun-Ying | Michels, Paul A.M. | Michiels, Carine | Mijaljica, Dalibor | Milojkovic, Ana | Minucci, Saverio | Miracco, Clelia | Miranti, Cindy K. | Mitroulis, Ioannis | Miyazawa, Keisuke | Mizushima, Noboru | Mograbi, Baharia | Mohseni, Simin | Molero, Xavier | Mollereau, Bertrand | Mollinedo, Faustino | Momoi, Takashi | Monastyrska, Iryna | Monick, Martha M. | Monteiro, Mervyn J. | Moore, Michael N. | Mora, Rodrigo | Moreau, Kevin | Moreira, Paula I. | Moriyasu, Yuji | Moscat, Jorge | Mostowy, Serge | Mottram, Jeremy C. | Motyl, Tomasz | Moussa, Charbel E.-H. | Müller, Sylke | Muller, Sylviane | Münger, Karl | Münz, Christian | Murphy, Leon O. | Murphy, Maureen E. | Musarò, Antonio | Mysorekar, Indira | Nagata, Eiichiro | Nagata, Kazuhiro | Nahimana, Aimable | Nair, Usha | Nakagawa, Toshiyuki | Nakahira, Kiichi | Nakano, Hiroyasu | Nakatogawa, Hitoshi | Nanjundan, Meera | Naqvi, Naweed I. | Narendra, Derek P. | Narita, Masashi | Navarro, Miguel | Nawrocki, Steffan T. | Nazarko, Taras Y. | Nemchenko, Andriy | Netea, Mihai G. | Neufeld, Thomas P. | Ney, Paul A. | Nezis, Ioannis P. | Nguyen, Huu Phuc | Nie, Daotai | Nishino, Ichizo | Nislow, Corey | Nixon, Ralph A. | Noda, Takeshi | Noegel, Angelika A. | Nogalska, Anna | Noguchi, Satoru | Notterpek, Lucia | Novak, Ivana | Nozaki, Tomoyoshi | Nukina, Nobuyuki | Nürnberger, Thorsten | Nyfeler, Beat | Obara, Keisuke | Oberley, Terry D. | Oddo, Salvatore | Ogawa, Michinaga | Ohashi, Toya | Okamoto, Koji | Oleinick, Nancy L. | Oliver, F. Javier | Olsen, Laura J. | Olsson, Stefan | Opota, Onya | Osborne, Timothy F. | Ostrander, Gary K. | Otsu, Kinya | Ou, Jing-hsiung James | Ouimet, Mireille | Overholtzer, Michael | Ozpolat, Bulent | Paganetti, Paolo | Pagnini, Ugo | Pallet, Nicolas | Palmer, Glen E. | Palumbo, Camilla | Pan, Tianhong | Panaretakis, Theocharis | Pandey, Udai Bhan | Papackova, Zuzana | Papassideri, Issidora | Paris, Irmgard | Park, Junsoo | Park, Ohkmae K. | Parys, Jan B. | Parzych, Katherine R. | Patschan, Susann | Patterson, Cam | Pattingre, Sophie | Pawelek, John M. | Peng, Jianxin | Perlmutter, David H. | Perrotta, Ida | Perry, George | Pervaiz, Shazib | Peter, Matthias | Peters, Godefridus J. | Petersen, Morten | Petrovski, Goran | Phang, James M. | Piacentini, Mauro | Pierre, Philippe | Pierrefite-Carle, Valérie | Pierron, Gérard | Pinkas-Kramarski, Ronit | Piras, Antonio | Piri, Natik | Platanias, Leonidas C. | Pöggeler, Stefanie | Poirot, Marc | Poletti, Angelo | Poüs, Christian | Pozuelo-Rubio, Mercedes | Prætorius-Ibba, Mette | Prasad, Anil | Prescott, Mark | Priault, Muriel | Produit-Zengaffinen, Nathalie | Progulske-Fox, Ann | Proikas-Cezanne, Tassula | Przedborski, Serge | Przyklenk, Karin | Puertollano, Rosa | Puyal, Julien | Qian, Shu-Bing | Qin, Liang | Qin, Zheng-Hong | Quaggin, Susan E. | Raben, Nina | Rabinowich, Hannah | Rabkin, Simon W. | Rahman, Irfan | Rami, Abdelhaq | Ramm, Georg | Randall, Glenn | Randow, Felix | Rao, V. Ashutosh | Rathmell, Jeffrey C. | Ravikumar, Brinda | Ray, Swapan K. | Reed, Bruce H. | Reed, John C. | Reggiori, Fulvio | Régnier-Vigouroux, Anne | Reichert, Andreas S. | Reiners, John J. | Reiter, Russel J. | Ren, Jun | Revuelta, José L. | Rhodes, Christopher J. | Ritis, Konstantinos | Rizzo, Elizete | Robbins, Jeffrey | Roberge, Michel | Roca, Hernan | Roccheri, Maria C. | Rocchi, Stephane | Rodemann, H. Peter | Rodríguez de Córdoba, Santiago | Rohrer, Bärbel | Roninson, Igor B. | Rosen, Kirill | Rost-Roszkowska, Magdalena M. | Rouis, Mustapha | Rouschop, Kasper M.A. | Rovetta, Francesca | Rubin, Brian P. | Rubinsztein, David C. | Ruckdeschel, Klaus | Rucker, Edmund B. | Rudich, Assaf | Rudolf, Emil | Ruiz-Opazo, Nelson | Russo, Rossella | Rusten, Tor Erik | Ryan, Kevin M. | Ryter, Stefan W. | Sabatini, David M. | Sadoshima, Junichi | Saha, Tapas | Saitoh, Tatsuya | Sakagami, Hiroshi | Sakai, Yasuyoshi | Salekdeh, Ghasem Hoseini | Salomoni, Paolo | Salvaterra, Paul M. | Salvesen, Guy | Salvioli, Rosa | Sanchez, Anthony M.J. | Sánchez-Alcázar, José A. | Sánchez-Prieto, Ricardo | Sandri, Marco | Sankar, Uma | Sansanwal, Poonam | Santambrogio, Laura | Saran, Shweta | Sarkar, Sovan | Sarwal, Minnie | Sasakawa, Chihiro | Sasnauskiene, Ausra | Sass, Miklós | Sato, Ken | Sato, Miyuki | Schapira, Anthony H.V. | Scharl, Michael | Schätzl, Hermann M. | Scheper, Wiep | Schiaffino, Stefano | Schneider, Claudio | Schneider, Marion E. | Schneider-Stock, Regine | Schoenlein, Patricia V. | Schorderet, Daniel F. | Schüller, Christoph | Schwartz, Gary K. | Scorrano, Luca | Sealy, Linda | Seglen, Per O. | Segura-Aguilar, Juan | Seiliez, Iban | Seleverstov, Oleksandr | Sell, Christian | Seo, Jong Bok | Separovic, Duska | Setaluri, Vijayasaradhi | Setoguchi, Takao | Settembre, Carmine | Shacka, John J. | Shanmugam, Mala | Shapiro, Irving M. | Shaulian, Eitan | Shaw, Reuben J. | Shelhamer, James H. | Shen, Han-Ming | Shen, Wei-Chiang
Autophagy  2012;8(4):445-544.
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
doi:10.4161/auto.19496
PMCID: PMC3404883  PMID: 22966490
LC3; autolysosome; autophagosome; flux; lysosome; phagophore; stress; vacuole
10.  A comprehensive glossary of autophagy-related molecules and processes (2nd edition) 
Autophagy  2011;7(11):1273-1294.
The study of autophagy is rapidly expanding, and our knowledge of the molecular mechanism and its connections to a wide range of physiological processes has increased substantially in the past decade. The vocabulary associated with autophagy has grown concomitantly. In fact, it is difficult for readers—even those who work in the field—to keep up with the ever-expanding terminology associated with the various autophagy-related processes. Accordingly, we have developed a comprehensive glossary of autophagy-related terms that is meant to provide a quick reference for researchers who need a brief reminder of the regulatory effects of transcription factors and chemical agents that induce or inhibit autophagy, the function of the autophagy-related proteins, and the roles of accessory components and structures that are associated with autophagy.
doi:10.4161/auto.7.11.17661
PMCID: PMC3359482  PMID: 21997368
autophagy; lysosome; mitophagy; pexophagy; stress; vacuole
11.  Cyclic AMP regulates formation of mammary epithelial acini in vitro 
Molecular Biology of the Cell  2012;23(15):2973-2981.
Cyclic AMP–dependent protein kinase A (PKA) is required for MCF10A mammary epithelial acinus formation in vitro. PKA plays a dual role by facilitating polarization of cells attached to the extracellular matrix and apoptosis of detached cells.
Epithelial cells form tubular and acinar structures notable for a hollow lumen. In three-dimensional culture utilizing MCF10A mammary epithelial cells, acini form due to integrin-dependent polarization and survival of cells contacting extracellular matrix (ECM), and the apoptosis of inner cells of acini lacking contact with the ECM. In this paper, we report that cyclic AMP (cAMP)-dependent protein kinase A (PKA) promotes acinus formation via two mechanisms. First, cAMP accelerates redistribution of α6-integrin to the periphery of the acinus and thus facilitates the polarization of outer acinar cells. Blocking of α6-integrin function by inhibitory antibody prevents cAMP-dependent polarization. Second, cAMP promotes the death of inner cells occupying the lumen. In the absence of cAMP, apoptosis is delayed, resulting in perturbed luminal clearance. cAMP-dependent apoptosis is accompanied by a posttranscriptional PKA-dependent increase in the proapoptotic protein Bcl-2 interacting mediator of cell death. These data demonstrate that cAMP regulates lumen formation in mammary epithelial cells in vitro, both through acceleration of polarization of outer cells and apoptosis of inner cells of the acinus.
doi:10.1091/mbc.E12-02-0078
PMCID: PMC3408423  PMID: 22675028
12.  Clinical Utility of LC3 and p62 Immunohistochemistry in Diagnosis of Drug-Induced Autophagic Vacuolar Myopathies: A Case-Control Study 
PLoS ONE  2012;7(4):e36221.
Background
Some patients treated with chloroquine, hydroxychloroquine, or colchicine develop autophagic vacuolar myopathy, the diagnosis of which currently requires electron microscopy. The goal of the current study was to develop an immunohistochemical diagnostic marker for this pathologic entity.
Methodology
Microtubule-associated protein light chain 3 (LC3) has emerged as a robust marker of autophagosomes. LC3 binds p62/SQSTM1, an adapter protein that is selectively degraded via autophagy. In this study, we evaluated the utility of immunohistochemical stains for LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar myopathy. The staining was performed on archival muscle biopsy material, with subject assignment to normal control, drug-treated control, and autophagic myopathy groups based on history of drug use and morphologic criteria.
Principal Findings
In all drug-treated subjects, but not in normal controls, LC3 and p62 showed punctate staining characteristic of autophagosome buildup. In the autophagic myopathy subjects, puncta were coarser and tended to coalesce into linear structures aligned with the longitudinal axis of the fiber, often in the vicinity of vacuoles. The percentage of LC3- and p62-positive fibers was significantly higher in the autophagic myopathy group compared to either the normal control (p<0.001) or the drug-treated control group (p<0.05). With the diagnostic threshold set between 8% and 15% positive fibers (depending on the desired level of sensitivity and specificity), immunohistochemical staining for either LC3 or p62 could be used to identify subjects with autophagic vacuolar myopathy within the drug-treated subject group (p≤0.001).
Significance
Immunohistochemistry for LC3 and p62 can facilitate tissue-based diagnosis of drug-induced autophagic vacuolar myopathies. By limiting the need for electron microscopy (a time consuming and costly technique with high specificity, but low sensitivity), clinical use of these markers will improve the speed and accuracy of diagnosis, resulting in significantly improved clinical care.
doi:10.1371/journal.pone.0036221
PMCID: PMC3338695  PMID: 22558391
13.  PERK Integrates Autophagy and Oxidative Stress Responses To Promote Survival during Extracellular Matrix Detachment▿  
Molecular and Cellular Biology  2011;31(17):3616-3629.
Mammary epithelial cells (MECs) detached from the extracellular matrix (ECM) produce deleterious reactive oxygen species (ROS) and induce autophagy to survive. The coordination of such opposing responses likely dictates whether epithelial cells survive ECM detachment or undergo anoikis. Here, we demonstrate that the endoplasmic reticulum kinase PERK facilitates survival of ECM-detached cells by concomitantly promoting autophagy, ATP production, and an antioxidant response. Loss-of-function studies show that ECM detachment activates a canonical PERK-eukaryotic translation initiation factor 2α (eIF2α)-ATF4-CHOP pathway that coordinately induces the autophagy regulators ATG6 and ATG8, sustains ATP levels, and reduces ROS levels to delay anoikis. Inducible activation of an Fv2E-ΔNPERK chimera by persistent activation of autophagy and reduction of ROS results in lumen-filled mammary epithelial acini. Finally, luminal P-PERK and LC3 levels are reduced in PERK-deficient mammary glands, whereas they are increased in human breast ductal carcinoma in situ (DCIS) versus normal breast tissues. We propose that the normal proautophagic and antioxidant PERK functions may be hijacked to promote the survival of ECM-detached tumor cells in DCIS lesions.
doi:10.1128/MCB.05164-11
PMCID: PMC3165554  PMID: 21709020
14.  ATG12-ATG3 and mitochondria 
Autophagy  2011;7(1):109-111.
doi:10.4161/auto.7.1.13998
PMCID: PMC3039733  PMID: 21068544
ATG12; ATG3; mitochondria; mitophagy; fusion; apoptosis
16.  Autophagy and Tumorigenesis 
Seminars in immunopathology  2010;32(4):383-396.
Autophagy, a catabolic process involved in the sequestration and lysosomal degradation of cytoplasmic contents, is crucial for cellular homeostasis. The current literature supports that autophagy plays diverse roles in the development, maintenance, and progression of tumors. While genetic evidence indicates autophagy functions as a tumor suppressor mechanism, it is also apparent that autophagy can promote the survival of established tumors under stress conditions and in response to chemotherapy. In this review, we discuss the mechanisms and the evidence underlying these multifaceted roles of autophagy in tumorigenesis, the prospects for targeting autophagy in cancer therapy, and overview the potential markers that may be utilized to reliably detect autophagy in clinical settings.
doi:10.1007/s00281-010-0213-0
PMCID: PMC2999728  PMID: 20589500
Autophagy; Cancer; Genome instability; Cell death; Chemotherapy
18.  Therapeutic implications of autophagy-mediated cell survival in gastrointestinal stromal tumor after treatment with imatinib mesylate 
Autophagy  2010;6(8):1190-1191.
doi:10.4161/auto.6.8.13430
PMCID: PMC3359491  PMID: 20930540
autophagy; GIST; KIT; PDGFRA; imatinib mesylate; small-molecule tyrosine kinase inhibitors; autophagy inhibitors
19.  The Multifaceted Roles of Autophagy In Tumors--Implications For Breast Cancer 
Autophagy is an evolutionarily conserved lysosomal degradation process that is crucial for adaptation to stress as well as in cellular homeostasis. In cancer, our current understanding has uncovered multifaceted roles for autophagy in tumor initiation and progression. Although genetic evidence corroborates a critical role for autophagy as a tumor suppressor mechanism, autophagy can also promote the survival and fitness of advanced tumors subject to stress, which has important implications during breast cancer progression and metastasis. Here, I discuss the mechanisms and the evidence underlying these diverse roles for autophagy in cancer and speculate on specific circumstances in which autophagy can be most effectively targeted for breast cancer treatment.
doi:10.1007/s10911-011-9223-3
PMCID: PMC3170851  PMID: 21779879
20.  ATG12 Conjugation to ATG3 Regulates Mitochondrial Homeostasis and Cell Death 
Cell  2010;142(4):590-600.
SUMMARY
ATG12, an ubiquitin-like modifier required for macroautophagy, has a single known conjugation target, another autophagy regulator called ATG5. Here, we identify ATG3 as a substrate for ATG12 conjugation. ATG3 is the E2-like enzyme necessary for ATG8/LC3 lipidation during autophagy. ATG12-ATG3 complex formation requires ATG7 as the E1 enzyme and ATG3 autocatalytic activity as the E2, resulting in the covalent linkage of ATG12 onto a single lysine on ATG3. Surprisingly, disrupting ATG12 conjugation to ATG3 does not affect starvation-induced autophagy. Rather, the lack of ATG12-ATG3 complex formation produces an expansion in mitochondrial mass and inhibits cell death mediated by mitochondrial pathways. Overall, these results unveil a role for ATG12-ATG3 in mitochondrial homeostasis, and implicate the ATG12 conjugation system in cellular functions distinct from the early steps of autophagosome formation.
doi:10.1016/j.cell.2010.07.018
PMCID: PMC2925044  PMID: 20723759
21.  Autophagy and Tumorigenesis 
FEBS letters  2009;584(7):1427-1435.
Autophagy, or cellular self-digestion, is activated in cancer cells in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance. Nonetheless, genetic evidence supports that autophagy functions as a tumor suppressor mechanism. Hence, the precise role of autophagy during cancer progression and treatment is both tissue and context dependent. Here, we discuss our current understanding of the biological functions of autophagy during cancer development, overview how autophagy is regulated by cancer-associated signaling pathways, and review how autophagy inhibition is being exploited to improve clinical outcomes.
doi:10.1016/j.febslet.2009.12.034
PMCID: PMC2843775  PMID: 20035753
Autophagy; cancer; genome instability; cell death; chemotherapy
22.  Autophagy and Metastasis: Another double-edged sword 
Current opinion in cell biology  2009;22(2):241-245.
In order to metastasize, tumor cells must adapt to untoward, stressful microenvironments as they disseminate into the systemic circulation and colonize distant organ sites. Autophagy, a tightly regulated lysosomal self-digestion process that is upregulated during cellular stress, has been demonstrated to suppress primary tumor formation, but how autophagy influences metastasis remains unknown. Autophagy may inhibit metastasis by promoting anti-tumor inflammatory responses or by restricting the expansion of dormant tumor cells into macrometastases. Conversely, self-eating may promote metastasis by enhancing tumor cell fitness in response to environmental stresses, such as anoikis, during metastatic progression. Because autophagy is titratable, it may serve both pro- and anti-metastatic functions depending on the contextual demands placed on tumor cells throughout the metastatic process.
doi:10.1016/j.ceb.2009.10.008
PMCID: PMC2854304  PMID: 19945838
23.  Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation 
Molecular Biology of the Cell  2011;22(2):165-178.
The protumor functions for autophagy are largely attributed to its ability to promote cancer cell survival in response to stress. This study demonstrates an unexpected connection between autophagy and glucose metabolism that facilitates adhesion-independent growth driven by a strong oncogenic insult—mutationally active Ras.
The protumorigenic functions for autophagy are largely attributed to its ability to promote cancer cell survival in response to diverse stresses. Here we demonstrate an unexpected connection between autophagy and glucose metabolism that facilitates adhesion-independent transformation driven by a strong oncogenic insult—mutationally active Ras. In cells ectopically expressing oncogenic H-Ras as well as human cancer cell lines harboring endogenous K-Ras mutations, autophagy is induced following extracellular matrix detachment. Inhibiting autophagy due to the genetic deletion or RNA interference–mediated depletion of multiple autophagy regulators attenuates Ras-mediated adhesion-independent transformation and proliferation as well as reduces glycolytic capacity. Furthermore, in contrast to autophagy-competent cells, both proliferation and transformation in autophagy-deficient cells expressing oncogenic Ras are insensitive to reductions in glucose availability. Overall, increased glycolysis in autophagy-competent cells facilitates Ras-mediated adhesion-independent transformation, suggesting a unique mechanism by which autophagy may promote Ras-driven tumor growth in specific metabolic contexts.
doi:10.1091/mbc.E10-06-0500
PMCID: PMC3020913  PMID: 21119005
24.  Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma 
Science signaling  2010;3(147):ra81.
Although the phosphatidylinositol 3-kinase to Akt to mammalian target of rapamycin (PI3K-Akt-mTOR) pathway promotes survival signaling, inhibitors of PI3K and mTOR induce minimal cell death in PTEN (phosphatase and tensin homolog deleted from chromosome 10 ) mutant glioma. Here, we show that the dual PI3K-mTOR inhibitor PI-103 induces autophagy in a form of glioma that is resistant to therapy. Inhibitors of autophagosome maturation cooperated with PI-103 to induce apoptosis through the mitochondrial pathway, indicating that the cellular self-digestion process of autophagy acted as a survival signal in this setting. Not all inhibitors of mTOR synergized with inhibitors of autophagy. Rapamycin delivered alone induced autophagy, yet cells survived inhibition of autophagosome maturation because of rapamycin-mediated activation of Akt. In contrast, adenosine 5′-triphosphate–competitive inhibitors of mTOR stimulated autophagy more potently than did rapamycin, with inhibition of mTOR complexes 1 and 2 contributing independently to induction of autophagy. We show that combined inhibition of PI3K and mTOR, which activates autophagy without activating Akt, cooperated with inhibition of autophagy to cause glioma cells to undergo apoptosis. Moreover, the PI3K-mTOR inhibitor NVP-BEZ235, which is in clinical use, synergized with the lysosomotropic inhibitor of autophagy, chloroquine, another agent in clinical use, to induce apoptosis in glioma xenografts in vivo, providing a therapeutic approach potentially translatable to humans.
doi:10.1126/scisignal.2001017
PMCID: PMC3001107  PMID: 21062993
25.  Autophagy and Tumorigenesis 
Seminars in Immunopathology  2010;32(4):383-396.
Autophagy, a catabolic process involved in the sequestration and lysosomal degradation of cytoplasmic contents, is crucial for cellular homeostasis. The current literature supports that autophagy plays diverse roles in the development, maintenance, and progression of tumors. While genetic evidence indicates autophagy functions as a tumor suppressor mechanism, it is also apparent that autophagy can promote the survival of established tumors under stress conditions and in response to chemotherapy. In this review, we discuss the mechanisms and the evidence underlying these multifaceted roles of autophagy in tumorigenesis, the prospects for targeting autophagy in cancer therapy, and overview the potential markers that may be utilized to reliably detect autophagy in clinical settings.
doi:10.1007/s00281-010-0213-0
PMCID: PMC2999728  PMID: 20589500
Autophagy; Cancer; Genome instability; Cell death; Chemotherapy

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