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1.  Phenethyl Isothiocyanate inhibits STAT3 activation in prostate cancer cells 
This study was undertaken to investigate the mechanism by which phenethyl isothiocyanate (PEITC), a natural compound from cruciferous vegetables, exhibits antitumor effect on prostate cancer cells. Cell proliferation, cell cycle, western blot, gene transfer and reporter assays were used to test the effects of PEITC on the growth and IL6/JAK/STAT3 pathway in prostate cancer. The result showed that PEITC significantly inhibited DU145 cell proliferation in a dose-dependent manner and induced the cell arrest at G2-M phase. PEITC inhibited both constitutive and interleukin 6 (IL-6)-induced STAT3 activity in DU145 cells. IL-6-stimulated phosphorylation of JAK2, an STAT3 upstream kinase, was also attenuated by PEITC. Moreover, an antioxidant reagent, N-acetyl-l-cysteine (NAC) which suppresses reactive oxygen species (ROS) generation, reversed the early inhibitory effects of PEITC on cell proliferation, constitutive or IL-6-mediated JAK-STAT3 phosphorylation in PCa cells. Taken together, our data demonstrated that PEITC can inhibit the activation of the JAK-STAT3 signal-cascade in prostate cancer cells and the underlying mechanism may be partially involved with blocking cellular ROS production during the early stage of the signaling activation by IL-6.
doi:10.1002/mnfr.200800253
PMCID: PMC3964815  PMID: 19437484
Phenethyl isothiocyanate; IL-6; STAT3; Androgen independent growth
2.  Vitamin D, Sunlight and Prostate Cancer Risk 
Prostate cancer is the second common cancer in men worldwide. The prevention of prostate cancer remains a challenge to researchers and clinicians. Here, we review the relationship of vitamin D and sunlight to prostate cancer risk. Ultraviolet radiation of the sunlight is the main stimulator for vitamin D production in humans. Vitamin D's antiprostate cancer activities may be involved in the actions through the pathways mediated by vitamin D metabolites, vitamin D metabolizing enzymes, vitamin D receptor (VDR), and VDR-regulated genes. Although laboratory studies including the use of animal models have shown that vitamin D has antiprostate cancer properties, whether it can effectively prevent the development and/or progression of prostate cancer in humans remains to be inconclusive and an intensively studied subject. This review will provide up-to-date information regarding the recent outcomes of laboratory and epidemiology studies on the effects of vitamin D on prostate cancer prevention.
doi:10.4061/2011/281863
PMCID: PMC3170721  PMID: 21991434
3.  PDLIM4, An Actin Binding Protein, Suppresses Prostate Cancer Cell Growth 
Cancer investigation  2009;27(3):264-272.
We investigated the molecular function of PDLIM4 in prostate cancer cells. PDLIM4 mRNA and protein-expression levels were reduced in LNCaP, LAPC4, DU145, CWR22, and PC3 prostate cancer cells. The re-expression of PDLIM4 in prostate cancer cells has significantly reduced the cell growth and clonogenicity with G1 phase of cell-cycle arrest. We have shown the direct interaction of PDLIM4 with F-actin. Restoration of PDLIM4 expression resulted in reduction of tumor growth in xenografts. These results suggest that PDLIM4 may function as a tumor suppressor, involved in the control of cell proliferation by associating with actin in prostate cancer cells.
doi:10.1080/07357900802406319
PMCID: PMC3086358  PMID: 19212833
Prostate cancer; Tumor suppressor gene; LIM domain protein; Cell growth; Actin cytoskeleton
4.  Hypermethylation of Genes for Diagnosis and Risk Stratification of Prostate Cancer 
Cancer investigation  2009;27(5):549-560.
To identify the relevant CpG sites as molecular markers, for the diagnosis and to distinguish the indolent and aggressive prostate tumors, we have determined the methylation status of 8 genes, including FLNC, EFS, ECRG4, RARB2, PITX2, GSTP1, PDLIM4, and KCNMA1 in 32 nonrecurrent, 32 recurrent primary prostate tumors, and 32 benign prostate tissues using EpiTYPER technology. Specific CpG site hypermethylation of RARB2 and GSTP1 CpG sites were useful for diagnosis of prostate cancer. Furthermore, CpG site hypermethylation of genes FLNC, EFS, ECRG4, PITX2, PDLIM4, and KCNMA1 were associated with prediction of biochemical, local, and systemic recurrence of prostate cancer.
doi:10.1080/07357900802620794
PMCID: PMC2693083  PMID: 19229700
CpG site methylation; Mass spectrometry assay; Prostate cancer; Recurrence prediction; Molecular markers
5.  Phenethyl isothiocyanate induces cell cycle arrest and reduction of α- and β- tubulin isotypes in human prostate cancer cells 
Cell biology international  2008;33(1):57-64.
This study was to investigate the effect of phenethyl isothiocyanate (PEITC), a constituent of many edible cruciferous vegetables, on the expression of α- and β- tubulins, which are the main components of microtubules in prostate cancer cells. Flow cytometry, light microscopy and western blot were used to study the cell cycle distribution, morphology changes and the expression of α- and β- tubulins in prostate cancer cells treated with PEITC. The results showed that PEITC induced G2- M cell phase arrest and inhibited the expression of α- and β- tubulin proteins in a number of human prostatic carcinoma cell lines. Further, it is showed that this inhibitory effect could be reversed by anti-oxidant N-acetyl cysteine and proteasome inhibitor MG132. Finally, it is concluded that PEITC inhibited the expression of α- and β- tubulins in prostate cancer cells, which is at least related to the oxygen reaction species and protein degradation.
doi:10.1016/j.cellbi.2008.09.013
PMCID: PMC2653099  PMID: 18957327
Phenethyl isothiocyanate; cell cycle; tubulin; prostate cancer
6.  Effect of geldanamycin on androgen receptor function and stability 
Cell Stress & Chaperones  2002;7(1):55-64.
In the ligand-binding inactive state, the steroid receptor heterocomplex contains Hsp90, Hsp70, high–molecular weight immunophilins, and other proteins. Hsp90 acts in association with co-chaperones to maintain the native state of the receptor within the cells. It was reported earlier that Hsp90 might not be as important for the androgen receptor (AR) activity as for the glucocorticoid receptor (GR) and the progesterone receptor (PR) activities. We used the Hsp90 inhibitor geldanamycin (GA) to explore the role of Hsp90 in the function of the AR heterocomplex. GA selectively binds to Hsp90 and inhibits its activity, leading to the loss of steroid receptor activity, and frequently, its degradation. In our study, LNCaP prostate cancer cells were treated with GA for 30 minutes or 24 hours, in the presence of mibolerone, a synthetic androgen. GA reduced the androgen-induced AR protein levels to 15 % after 24 hours of treatment. Several androgen up-regulated genes, including immunophilin FKBP51 and prostate specific antigen (PSA), were reduced by GA treatment. In cells treated with GA after transfection with a PSA promoter or an androgen response element–driven reporter gene, AR-mediated transactivation of reporter gene expression was reversibly inhibited by GA. Loss of androgen-binding ability and AR levels was attributed to reduced transcription of AR-regulated gene expression. Degradation rate of 35S-labeled AR was significantly increased by GA in the presence or absence of mibolerone. GA induced the degradation of AR through the proteasomal pathway. AR in cells treated with proteasomal inhibitor lactacystin, was insoluble in Nonidet P-40 (NP40)-based buffer and could not restore the androgen-binding ability. We report here that GA treatment disrupted both hormone-binding activity and receptor protein stability, resulting in a dramatic loss of androgen-induced gene activation. These results show that Hsp90 activity is important for both the chaperone-mediated folding of the AR into a high-affinity ligand-binding conformation and the functional activity of the AR.
PMCID: PMC514802  PMID: 11894840
7.  Riccardin D Exerts Its Antitumor Activity by Inducing DNA Damage in PC-3 Prostate Cancer Cells In Vitro and In Vivo 
PLoS ONE  2013;8(9):e74387.
We recently reported that Riccardin D (RD) was able to induce apoptosis by targeting Topo II. Here, we found that RD induced cell cycle arrest in G2/M phase in PC-3 cells, and caused remarkable DNA damage as evidenced by induction of γH2AX foci, micronuclei, and DNA fragmentation in Comet assay. Time kinetic and dose-dependent studies showed that ATM/Chk2 and ATR/Chk1 signaling pathways were sequentially activated in response to RD. Blockage of ATM/ATR signaling led to the attenuation of RD-induced γH2AX, and to the partial recovery of cell proliferation. Furthermore, RD exposure resulted in the inactivation of BRCA1, suppression of HR and NHEJ repair activity, and downregulation of the expressions and DNA-end binding activities of Ku70/86. Consistent with the observations, microarray data displayed that RD triggered the changes in genes responsible for cell proliferation, cell cycle, DNA damage and repair, and apoptosis. Administration of RD to xenograft mice reduced tumor growth, and coordinately caused alterations in the expression of genes involved in DNA damage and repair, along with cell apoptosis. Thus, this finding identified a novel mechanism by which RD affects DNA repair and acts as a DNA damage agent in prostate cancer.
doi:10.1371/journal.pone.0074387
PMCID: PMC3775815  PMID: 24069304
8.  Antiangiogenic Effects and Therapeutic Targets of Azadirachta indica Leaf Extract in Endothelial Cells 
Azadirachta indica (common name: neem) leaves have been found to possess immunomodulatory, anti-inflammatory and anti-carcinogenic properties. The present study evaluates anti-angiogenic potential of ethanol extract of neem leaves (EENL) in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with EENL inhibited VEGF induced angiogenic response in vitro and in vivo. The in vitro proliferation, invasion and migration of HUVECs were suppressed with EENL. Nuclear fragmentation and abnormally small mitochondria with dilated cristae were observed in EENL treated HUVECs by transmission electron microscopy. Genome-wide mRNA expression profiling after treatment with EENL revealed differentially regulated genes. Expression changes of the genes were validated by quantitative real-time polymerase chain reaction. Additionally, increase in the expression of HMOX1, ATF3 and EGR1 proteins were determined by immunoblotting. Analysis of the compounds in the EENL by mass spectrometry suggests the presence of nimbolide, 2′,3′-dehydrosalannol, 6-desacetyl nimbinene and nimolinone. We further confirmed antiproliferative activity of nimbolide and 2′,3′-dehydrosalannol in HUVECs. Our results suggest that EENL by regulating the genes involved in cellular development and cell death functions could control cell proliferation, attenuate the stimulatory effects of VEGF and exert antiangiogenic effects. EENL treatment could have a potential therapeutic role during cancer progression.
doi:10.1155/2012/303019
PMCID: PMC3296311  PMID: 22461839
9.  Novel Molecular Targets of Azadirachta indica Associated with Inhibition of Tumor Growth in Prostate Cancer 
The AAPS Journal  2011;13(3):365-377.
Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models. Analysis of the components in the EENL by mass spectrometry suggests the presence of 2′,3′-dehydrosalannol, 6-desacetyl nimbinene, and nimolinone. Treatment of C4-2B and PC-3M-luc2 prostate cancer cells with EENL inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with EENL treatment in prostate cancer cells. Functional analysis unveiled that most of the up-regulated genes were associated with cell death, and drug metabolism, and the down-regulated genes were associated with cell cycle, DNA replication, recombination, and repair functions. Quantitative PCR confirmed significant up-regulation of 40 genes and immunoblotting revealed increase in the protein expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10. EENL treatment inhibited the growth of C4-2B and PC-3M-luc2 prostate cancer xenografts in nude mice. The suppression of tumor growth is associated with the formation of hyalinized fibrous tumor tissue and the induction of cell death by apoptosis. These results suggest that EENL-containing natural bioactive compounds could have potent anticancer property and the regulation of multiple cellular pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-011-9279-4) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-011-9279-4
PMCID: PMC3144372  PMID: 21560017
gene expression profiles; neem leaf extract; therapeutic targets and prostate cancer; tumor models
10.  Novel Molecular Targets of Azadirachta indica Associated with Inhibition of Tumor Growth in Prostate Cancer 
The AAPS Journal  2011;13(3):365-377.
Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models. Analysis of the components in the EENL by mass spectrometry suggests the presence of 2′,3′-dehydrosalannol, 6-desacetyl nimbinene, and nimolinone. Treatment of C4-2B and PC-3M-luc2 prostate cancer cells with EENL inhibited the cell proliferation. Genome-wide expression profiling, using oligonucleotide microarrays, revealed genes differentially expressed with EENL treatment in prostate cancer cells. Functional analysis unveiled that most of the up-regulated genes were associated with cell death, and drug metabolism, and the down-regulated genes were associated with cell cycle, DNA replication, recombination, and repair functions. Quantitative PCR confirmed significant up-regulation of 40 genes and immunoblotting revealed increase in the protein expression levels of HMOX1, AKR1C2, AKR1C3, and AKR1B10. EENL treatment inhibited the growth of C4-2B and PC-3M-luc2 prostate cancer xenografts in nude mice. The suppression of tumor growth is associated with the formation of hyalinized fibrous tumor tissue and the induction of cell death by apoptosis. These results suggest that EENL-containing natural bioactive compounds could have potent anticancer property and the regulation of multiple cellular pathways could exert pleiotrophic effects in prevention and treatment of prostate cancer.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-011-9279-4) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-011-9279-4
PMCID: PMC3144372  PMID: 21560017
gene expression profiles; neem leaf extract; therapeutic targets and prostate cancer; tumor models
11.  Oxidative Stress and DNA Methylation in Prostate Cancer 
The protective effects of fruits, vegetables, and other foods on prostate cancer may be due to their antioxidant properties. An imbalance in the oxidative stress/antioxidant status is observed in prostate cancer patients. Genome oxidative damage in prostate cancer patients is associated with higher lipid peroxidation and lower antioxidant levels. Oxygen radicals are associated with different steps of carcinogenesis, including structural DNA damage, epigenetic changes, and protein and lipid alterations. Epigenetics affects genetic regulation, cellular differentiation, embryology, aging, cancer, and other diseases. DNA methylation is perhaps the most extensively studied epigenetic modification, which plays an important role in the regulation of gene expression and chromatin architecture, in association with histone modification and other chromatin-associated proteins. This review will provide a broad overview of the interplay of oxidative stress and DNA methylation, DNA methylation changes in regulation of gene expression, lifestyle changes for prostate cancer prevention, DNA methylation as biomarkers for prostate cancer, methods for detection of methylation, and clinical application of DNA methylation inhibitors for epigenetic therapy.
doi:10.1155/2010/302051
PMCID: PMC2910495  PMID: 20671914
12.  Sodium selenite inhibits interleukin-6-mediated androgen receptor activation in prostate cancer cells via upregulation of c-Jun 
Background
It has been suggested that interleukin-6 (IL-6) may modulate androgen receptor (AR) action to accelerate prostate cancer (PCa) progression. Selenium compounds are highly recommended as a promising chemopreventive agent for PCa. This study was to determine if selenium can repress IL-6 mediated AR action in PCa progression.
Methods
Cell proliferation, prostate-specific antigen, gene transfer, and western blot assays were used to study the effects of sodium selenite and methylseleninic acid on IL-6 mediated AR action on an AR expressing human prostate cancer cell line, LNCaP.
Results
We found that sodium selenite, but not methylseleninic acid, significantly (p < 0.05) inhibited IL-6-induced trans-activating activity of AR and cell proliferation in LNCaP cells. Interestingly, although sodium selenite did not show effect on activation of both STAT3 and ERK1/2 in the presence of IL-6, an increased expression of c-Jun was detected in cells after treatment with sodium selenite. Indeed, we showed overexpression of c-Jun blocked IL-6-induced AR activation.
Conclusions
Taken together, our results suggest that sodium selenite not methylseleninic acid can inhibit IL-6-mediated AR activation by increased c-Jun in LNCaP cells. Sodium selenite may be a proper selenium form for further testing its potency on intervening IL-6-mediated PCa progression.
doi:10.1016/j.cca.2007.01.031
PMCID: PMC1955324  PMID: 17346688
Selenium; IL-6; prostate cancer; c-Jun; androgen independent growth
13.  Retigeric Acid B Exhibits Antitumor Activity through Suppression of Nuclear Factor-κB Signaling in Prostate Cancer Cells in Vitro and in Vivo 
PLoS ONE  2012;7(5):e38000.
Previously, we reported that retigeric acid B (RB), a natural pentacyclic triterpenic acid isolated from lichen, inhibited cell growth and induced apoptosis in androgen-independent prostate cancer (PCa) cells. However, the mechanism of action of RB remains unclear. In this study, we found that using PC3 and DU145 cells as models, RB inhibited phosphorylation levels of IκBα and p65 subunit of NF-κB in a time- and dosage-dependent manner. Detailed study revealed that RB blocked the nuclear translocation of p65 and its DNA binding activity, which correlated with suppression of NF-κB-regulated proteins including Bcl-2, Bcl-xL, cyclin D1 and survivin. NF-κB reporter assay suggested that RB was able to inhibit both constitutive activated-NF-κB and LPS (lipopolysaccharide)-induced activation of NF-κB. Overexpression of RelA/p65 rescued RB-induced cell death, while knockdown of RelA/p65 significantly promoted RB-mediated inhibitory effect on cell proliferation, suggesting the crucial involvement of NF-κB pathway in this event. We further analyzed antitumor activity of RB in in vivo study. In C57BL/6 mice carrying RM-1 homografts, RB inhibited tumor growth and triggered apoptosis mainly through suppressing NF-κB activity in tumor tissues. Additionally, DNA microarray data revealed global changes in the gene expression associated with cell proliferation, apoptosis, invasion and metastasis in response to RB treatment. Therefore, our findings suggested that RB exerted its anti-tumor effect by targeting the NF-κB pathway in PCa cells, and this could be a general mechanism for the anti-tumor effect of RB in other types of cancers as well.
doi:10.1371/journal.pone.0038000
PMCID: PMC3362538  PMID: 22666431

Results 1-13 (13)