PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-10 (10)
 

Clipboard (0)
None

Select a Filter Below

Journals
Authors
more »
Year of Publication
Document Types
1.  CAPER, a novel regulator of human breast cancer progression 
Cell Cycle  2014;13(8):1256-1264.
CAPER is an estrogen receptor (ER) co-activator that was recently shown to be involved in human breast cancer pathogenesis. Indeed, we reported increased expression of CAPER in human breast cancer specimens. We demonstrated that CAPER was undetectable or expressed at relatively low levels in normal breast tissue and assumed a cytoplasmic distribution. In contrast, CAPER was expressed at higher levels in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) specimens, where it assumed a predominantly nuclear distribution. However, the functional role of CAPER in human breast cancer initiation and progression remained unknown. Here, we used a lentiviral-mediated gene silencing approach to reduce the expression of CAPER in the ER-positive human breast cancer cell line MCF-7. The proliferation and tumorigenicity of MCF-7 cells stably expressing control or human CAPER shRNAs was then determined via both in vitro and in vivo experiments. Knockdown of CAPER expression significantly reduced the proliferation of MCF-7 cells in vitro. Importantly, nude mice injected with MCF-7 cells harboring CAPER shRNAs developed smaller tumors than mice injected with MCF-7 cells harboring control shRNAs. Mechanistically, tumors derived from mice injected with MCF-7 cells harboring CAPER shRNAs displayed reduced expression of the cell cycle regulators PCNA, MCM7, and cyclin D1, and the protein synthesis marker 4EBP1. In conclusion, knockdown of CAPER expression markedly reduced human breast cancer cell proliferation in both in vitro and in vivo settings. Mechanistically, knockdown of CAPER abrogated the activity of proliferative and protein synthesis pathways.
doi:10.4161/cc.28156
PMCID: PMC4049962  PMID: 24621503
CAPER; breast cancer; estrogen receptor; proliferation; tumor growth
2.  Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development 
Introduction
Previous studies have identified cholesterol as an important regulator of breast cancer development. High-density lipoprotein (HDL) and its cellular receptor, the scavenger receptor class B type I (SR-BI) have both been implicated in the regulation of cellular cholesterol homeostasis, but their functions in cancer remain to be established.
Methods
In the present study, we have examined the role of HDL and SR-BI in the regulation of cellular signaling pathways in breast cancer cell lines and in the development of tumor in a mouse xenograft model.
Results
Our data show that HDL is capable of stimulating migration and can activate signal transduction pathways in the two human breast cancer cell lines, MDA-MB-231 and MCF7. Furthermore, we also show that knockdown of the HDL receptor, SR-BI, attenuates HDL-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (Akt) pathway in both cell lines. Additional investigations show that inhibition of the PI3K pathway, but not that of the mitogen-activated protein kinase (MAPK) pathway, could lead to a reduction in cellular proliferation in the absence of SR-BI. Importantly, whereas the knockdown of SR-BI led to decreased proliferation and migration in vitro, it also led to a significant reduction in tumor growth in vivo. Most important, we also show that pharmacological inhibition of SR-BI can attenuate signaling and lead to decreased cellular proliferation in vitro. Taken together, our data indicate that both cholesteryl ester entry via HDL-SR-BI and Akt signaling play an essential role in the regulation of cellular proliferation and migration, and, eventually, tumor growth.
Conclusions
These results identify SR-BI as a potential target for the treatment of breast cancer.
doi:10.1186/bcr3483
PMCID: PMC3978612  PMID: 24060386
3.  Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and Metastasis via Oxidative Stress, Mitophagy, and Aerobic Glycolysis 
Antioxidants & Redox Signaling  2012;16(11):1264-1284.
Abstract
Significance: Here, we review certain recent advances in oxidative stress and tumor metabolism, which are related to understanding the contributions of the microenvironment in promoting tumor growth and metastasis. In the early 1920s, Otto Warburg, a Nobel Laureate, formulated a hypothesis to explain the “fundamental basis” of cancer, based on his observations that tumors displayed a metabolic shift toward glycolysis. In 1963, Christian de Duve, another Nobel Laureate, first coined the phrase auto-phagy, derived from the Greek words “auto” and “phagy,” meaning “self” and “eating.” Recent Advances: Now, we see that these two ideas (autophagy and aerobic glycolysis) physically converge in the tumor stroma. First, cancer cells secrete hydrogen peroxide. Then, as a consequence, oxidative stress in cancer-associated fibroblasts drives autophagy, mitophagy, and aerobic glycolysis. Critical Issues: This “parasitic” metabolic coupling converts the stroma into a “factory” for the local production of recycled and high-energy nutrients (such as L-lactate)—to fuel oxidative mitochondrial metabolism in cancer cells. We believe that Warburg and de Duve would be pleased with this new two-compartment model for understanding tumor metabolism. It adds a novel stromal twist to two very well-established cancer paradigms: aerobic glycolysis and autophagy. Future Directions: Undoubtedly, these new metabolic models will foster the development of novel biomarkers, and corresponding therapies, to achieve the goal of personalized cancer medicine. Given the central role that oxidative stress plays in this process, new powerful antioxidants should be developed in the fight against cancer. Antioxid. Redox Signal. 16, 1264–1284.
doi:10.1089/ars.2011.4243
PMCID: PMC3324816  PMID: 21883043
4.  Tryptophan hydroxylase-1 regulates immune tolerance and inflammation 
The Journal of Experimental Medicine  2012;209(11):2127-2135.
Tryptophan hydroxylase deficiency in mast cells breaks allograft tolerance, induces tumor remission, and intensifies neuroinflammation.
Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control inflammatory responses and immune tolerance. Here we report the novel finding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 deficiency breaks allograft tolerance, induces tumor remission, and intensifies neuroinflammation, respectively. All of these effects of Tph-1 deficiency are independent of its downstream product serotonin. Because mast cells (MCs) appear to be the major source of Tph-1 and restoration of Tph-1 in the MC compartment in vivo compensates for the defect, these experiments introduce a fundamentally new mechanism of MC-mediated immune suppression that broadly impacts multiple arms of immunity.
doi:10.1084/jem.20120408
PMCID: PMC3478935  PMID: 23008335
5.  Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide 
Cell Cycle  2013;12(10):1510-1520.
Caveolin-1 (Cav-1) is a critical regulator of tumor progression in a variety of cancers where it has been shown to act as either a tumor suppressor or tumor promoter. In glioblastoma multiforme, it has been previously demonstrated to function as a putative tumor suppressor. Our studies here, using the human glioblastoma-derived cell line U-87MG, further support the role of Cav-1 as a negative regulator of tumor growth. Using a lentiviral transduction approach, we were able to stably overexpress Cav-1 in U-87MG cells. Gene expression microarray analyses demonstrated significant enrichment in gene signatures corresponding to downregulation of MAPK, PI3K/AKT and mTOR signaling, as well as activation of apoptotic pathways in Cav-1-overexpressing U-87MG cells. These same gene signatures were later confirmed at the protein level in vitro. To explore the ability of Cav-1 to regulate tumor growth in vivo, we further show that Cav-1-overexpressing U-87MG cells display reduced tumorigenicity in an ectopic xenograft mouse model, with marked hypoactivation of MAPK and PI3K/mTOR pathways. Finally, we demonstrate that Cav-1 overexpression confers sensitivity to the most commonly used chemotherapy for glioblastoma, temozolomide. In conclusion, Cav-1 negatively regulates key cell growth and survival pathways and may be an effective biomarker for predicting response to chemotherapy in glioblastoma.
doi:10.4161/cc.24497
PMCID: PMC3680531  PMID: 23598719
Caveolin-1; glioma; brain cancer; tumor progression; tumor suppressor; microarray; mouse model; chemotherapy; temozolomide
6.  The autophagic tumor stroma model of cancer or “battery-operated tumor growth” 
Cell Cycle  2010;9(21):4297-4306.
The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the “Autophagy Paradox.” We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm “The Autophagic Tumor Stroma Model of Cancer Cell Metabolism” or “Battery-Operated Tumor Growth.” In this sense, autophagy in the tumor stroma serves as a “battery” to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients—both effectively “starving” cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy by the upregulation of natural, endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a “lethal” aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia.
doi:10.4161/cc.9.21.13817
PMCID: PMC3055183  PMID: 21051947
caveolin-1; autophagy; cancer associated fibroblasts; hypoxia; mitophagy; oxidative stress; DNA damage; genomic instability; tumor stroma; wasting (cancer cachexia); Warburg effect
7.  Clinical and Translational Implications for the Caveolin Gene Family: Lessons from Mouse Models and Human Genetic Disorders 
Here, we review the clinical and translational implications of the caveolin gene family for understanding the pathogenesis of human diseases, including breast and prostate cancers, pulmonary hypertension, cardiomyopathy, diabetes, and muscular dystrophy. Detailed phenotypic analysis of caveolin knock-out mice has served to highlight the crucial role of a caveolin-deficiency in the pathogenesis of many human disease processes. Mutations in the human caveolin genes are associated with a number of established genetic disorders (such as breast cancer, lipodystrophy, muscular dystrophy, and cardiomyopathy), making the caveolins important and novel targets for drug development. The implementation of new strategies for caveolin-replacement therapy—including caveolin-mimetic peptides—is ongoing.
doi:10.1038/labinvest.2009.23
PMCID: PMC2796209  PMID: 19333235
Caveolae; Caveolins; Human Disease Pathogenesis; Mouse Animal Models
8.  Interleukin-17 is a negative regulator of established allergic asthma 
The Journal of Experimental Medicine  2006;203(12):2715-2725.
T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R–deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenous IL-17 reduced pulmonary eosinophil recruitment and bronchial hyperreactivity, demonstrating a novel regulatory role of IL-17. Mechanistically, IL-17 down modulated eosinophil-chemokine eotaxin (CCL11) and thymus- and activation-regulated chemokine/CCL17 (TARC) in lungs in vivo and ex vivo upon antigen restimulation. In vitro, IL-17 reduced TARC production in dendritic cells (DCs)—the major source of TARC—and antigen uptake by DCs and IL-5 and IL-13 production in regional lymph nodes. Furthermore, IL-17 is regulated in an IL-4–dependent manner since mice deficient for IL-4Rα signaling showed a marked increase in IL-17 concentration with inhibited eosinophil recruitment. Therefore, endogenous IL-17 is controlled by IL-4 and has a dual role. Although it is essential during antigen sensitization to establish allergic asthma, in sensitized mice IL-17 attenuates the allergic response by inhibiting DCs and chemokine synthesis.
doi:10.1084/jem.20061401
PMCID: PMC2118159  PMID: 17101734
9.  Hyper-reactivity of cerebral arteries from ovariectomized rats: therapeutic benefit of tamoxifen 
British Journal of Pharmacology  2003;140(7):1187-1192.
An increased incidence of systemic hypertension has been documented in postmenopausal women and identified as an independent risk factor in the development of cerebrovascular stroke. The present study examined whether cerebrovascular reactivity was increased in the hypertensive ovariectomized rat, and explored the potential therapeutic benefit of the partial estrogen receptor agonist tamoxifen.Female Sprague–Dawley rats were subjected to bilateral ovariectomy (OVX, n=16) or a sham operation (n=8). At 6-week postsurgery, rats were anesthetized to assess ventricular contractility and blood pressure. In a second series of experiments, OVX rats (n=8) were given tamoxifen starting 3 weeks postsurgery, and continued for 3 weeks. At the end of each protocol, the middle cerebral artery was harvested and rings were mounted in wire-myographs to measure isometric tension.Systolic arterial pressure (SAP) was significantly increased (P<0.05) in the OVX rat (174±8 mmHg), as compared to sham (135±6 mmHg). The resting tension of isolated cerebral arteries from OVX rats (186±15 mg) was significantly elevated (P<0.05), as compared to sham (129±9 mg). Phenylephrine treatment did not elicit a constriction of cerebral arteries isolated from sham rats, whereas a potent response (P<0.05) was observed in OVX rats. Nitric oxide (NO) synthase inhibition with L-NNA led to a limited contraction in sham rats (8±3% of Emax), whereas a significant (P<0.05) increase was observed in OVX rats (34±12% of Emax). Lastly, vascular sensitivity (pD2) to sodium nitroprusside was significantly increased (P<0.05) in OVX rats, as compared to sham.Tamoxifen therapy normalized the resting tension of isolated cerebral arteries from OVX rats, abrogated phenylephrine-mediated contraction, and modestly reduced SAP. By contrast, tamoxifen treatment of OVX rats did not attenuate L-NNA-mediated contractile response of cerebral arteries.These data demonstrate that the cerebral artery isolated from the OVX rat was associated with an exaggerated vasoconstrictor response to phenylephrine, and altered NO-dependent vascular reactivity. The administration of tamoxifen to OVX rats normalized cerebral artery reactivity to phenylephrine. These findings provide the impetus to examine the potential therapeutic benefit of the partial estrogen receptor agonist tamoxifen to reduce the incidence of cerebrovascular stroke in postmenopausal women.
doi:10.1038/sj.bjp.0705547
PMCID: PMC1574134  PMID: 14597597
Cerebral arteries; endothelin-1; α1-adrenergic receptors; nitric oxide; tamoxifen; ovariectomy
10.  Elevated mean arterial pressure in the ovariectomized rat was normalized by ETA receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis 
British Journal of Pharmacology  2002;136(5):685-692.
The influence of menopause on ventricular function and remodelling remains undefined. The following study examined the effect of ovariectomy on ventricular contractility, cardiac hypertrophy and extracellular matrix protein expression.Elevated circulating levels of the vasoconstrictor endothelin-1 have been reported in post-menopausal women. Moreover, endothelin-1 has been shown to influence blood pressure, ventricular function and cardiac remodelling. In this regard, the potential pathophysiological role of endothelin-1 in the ovariectomized rat was assessed via the administration of the selective endothelinA receptor (ETA) antagonist BMS-182874.In 3 and 6 week ovariectomized female Sprague – Dawley rats, uterus atrophy was associated with a significant increase in mean arterial pressure, and left ventricular systolic pressure, as compared to sham. By contrast, right ventricular contractile indices were normal in the ovariectomized rat. Despite increased systolic load, left ventricular hypertrophy was not evident, prepro-atrial natriuretic peptide (prepro-ANP) mRNA levels and collagen protein content were similar to sham.The treatment of ovariectomized rats with BMS-182874 (60 mg kg−1 per day) did not reverse uterus atrophy. However, BMS-182874 normalized mean arterial pressure, and left ventricular systolic pressure in the ovariectomized rat.Thus, despite elevated blood pressure, ovariectomized rats were not associated with either cardiac hypertrophy or fibrosis. Lastly, endothelin-1, acting via the stimulation of the ETA receptor represents an integral mechanism implicated in the increase of mean arterial pressure following ovariectomy.
doi:10.1038/sj.bjp.0704765
PMCID: PMC1573395  PMID: 12086977
Ovariectomy; hypertension; cardiac hypertrophy; fibrosis; endothelin-1

Results 1-10 (10)