Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer is the most predominant cancer in men and related death rate increases every year. Till date, there is no effective therapy for androgen independent prostate cancer. Previous studies reported that aged garlic extract suppresses cancer growth. In the present study, diallyl disulfide [DADS], oil soluble organosulfur compound of garlic, was studied for its antiproliferative and induction of cell cycle arrest on prostate cancer cells in vitro. The suppression of cell growth was assessed by MTT assay. Induction of cell cycle arrest was assessed and confirmed by propidium iodide staining in flowcytometric analysis and western blotting analysis of major cell cycle regulator proteins. The results showed that DADS inhibited the growth of prostate cancer cells in a dose dependent manner, compared to the control. At 25 microM and 40 microM concentrations, DADS induced cell cycle arrest at G2/M transition in PC-3 cells. Western blotting analysis of cyclin A, B(1) and cyclin dependent kinase 1 [CDK1] revealed that DADS inhibited the cell cycle by downregulating CDK1 expression. It is concluded that DADS, inhibits proliferation of prostate cancer cells through cell cycle arrest. Dose dependent effect of DADS on PC-3 cell line was observed in the present study.
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PMID:Garlic compound, diallyl disulfide induces cell cycle arrest in prostate cancer cell line PC-3. 1669 15

The function of cyclin D1 as a positive regulator of the cell cycle and proto-oncogene has been well established. Cyclin D1 elicits its pro-proliferative function early in G1 phase, through its ability to activate cyclin dependent kinase (CDK) 4 or 6. Active CDK4/6-cyclin D1 complexes phosphorylate substrates that are critical for modulating G1 to S phase progression, and in this manner promote cellular proliferation. Emerging data from a number of model systems revealed that cyclin D1 also holds multiple, kinase-independent cellular functions. First, cyclin D1 assists in sequestering CDK inhibitors (e.g. p27kip1), thus bolstering late G1 CDK activity. Second, cyclin D1 is known to bind and modulate the action of several transcription factors that hold significance in human cancers. Thus, cyclin D1 impinges on several distinct pathways that govern cancer cell proliferation. Although intragenic somatic mutation of cyclin D1 in human disease is rare, cyclin D1 gene translocation, amplification and/or overexpression are frequent events in selected tumor types. Additionally, a polymorphism in the cyclin D1 locus that may affect splicing has been implicated in increased cancer risk or poor outcome. Recent functional analyses of an established cyclin D1 splice variant, cyclin D1b, revealed that the cyclin D1b isoform harbors unique activities in cancer cells. Here, we review the literature implicating cyclin D1b as a mediator of aberrant cellular proliferation in cancer. The differential roles of cyclin D1 and the cyclin D1b splice variant in prostate cancer will be also be addressed, wherein divergent functions have been linked to altered proliferative control.
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PMID:The cyclin D1b splice variant: an old oncogene learns new tricks. 1686 92

Androgen receptors (ARs) are phosphorylated at multiple sites in response to ligand binding, but the kinases mediating AR phosphorylation and the importance of these kinases in AR function have not been established. Here we show that cyclin-dependent kinase 1 (Cdk1) mediates AR phosphorylation at Ser-81 and increases AR protein expression, and that Cdk1 inhibitors decrease AR Ser-81 phosphorylation, protein expression, and transcriptional activity in prostate cancer (PCa) cells. The decline in AR protein expression mediated by the Cdk inhibitor roscovitine was prevented by proteosome inhibitors, indicating that Cdk1 stabilizes AR protein, although roscovitine also decreased AR message levels. Analysis of an S81A AR mutant demonstrated that this site is not required for transcriptional activity or Cdk1-mediated AR stabilization in transfected cells. The AR is active and seems to be stabilized by low levels of androgen in "androgen-independent" PCas that relapse subsequent to androgen-deprivation therapy. Significantly, the expression of cyclin B and Cdk1 was increased in these tumors, and treatment with roscovitine abrogated responses to low levels of androgen in the androgen-independent C4-2 PCa cell line. Taken together, these findings identify Cdk1 as a Ser-81 kinase and indicate that Cdk1 stabilizes AR protein by phosphorylation at a site(s) distinct from Ser-81. Moreover, these results indicate that increased Cdk1 activity is a mechanism for increasing AR expression and stability in response to low androgen levels in androgen-independent PCas, and that Cdk1 antagonists may enhance responses to androgen-deprivation therapy.
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PMID:Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. 1704 41

We recently reported that gallic acid is a major active agent responsible for grape seed extract activity in DU145 human prostate carcinoma cells. The present study was conducted to examine its efficacy and associated mechanism. Gallic acid treatment of DU145 cells resulted in a strong cell growth inhibition, cell cycle arrest, and apoptotic death in a dose- and time-dependent manner, together with a decrease in cyclin-dependent kinases and cyclins but strong induction in Cip1/p21. Additional mechanistic studies showed that gallic acid induces an early Tyr(15) phosphorylation of cell division cycle 2 (cdc2). Further upstream, gallic acid also induced phosphorylation of both cdc25A and cdc25C via ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) activation as a DNA damage response evidenced by increased phospho-histone 2AX (H2A.X) that is phosphorylated by ATM in response to DNA damage. Time kinetics of ATM phosphorylation, together with those of H2A.X and Chk2, was in accordance with an inactivating phosphorylation of cdc25A and cdc25C phosphatases and cdc2 kinase, suggesting that gallic acid increases cdc25A/C-cdc2 phosphorylation and thereby inactivation via ATM-Chk2 pathway following DNA damage that induces cell cycle arrest. Caffeine, an ATM/ataxia telangiectasia-rad3-related inhibitor, reversed gallic acid-caused ATM and H2A.X phosphorylation and cell cycle arrest, supporting the role of ATM pathway in gallic acid-induced cell cycle arrest. Additionally, gallic acid caused caspase-9, caspase-3, and poly(ADP)ribose polymerase cleavage, but pan-caspase inhibitor did not reverse apoptosis, suggesting an additional caspase-independent apoptotic mechanism. Together, this is the first report identifying gallic acid efficacy and associated mechanisms in an advanced and androgen-independent human prostate carcinoma DU145 cells, suggesting future in vivo efficacy studies with this agent in preclinical prostate cancer models.
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PMID:Gallic acid causes inactivating phosphorylation of cdc25A/cdc25C-cdc2 via ATM-Chk2 activation, leading to cell cycle arrest, and induces apoptosis in human prostate carcinoma DU145 cells. 1717 33

Chemotherapeutic drugs ideally should take advantage of the differences between transformed and normal cells and induce apoptosis only in cancer cells. One such difference may be the overexpression of cyclin B1 protein in cancer cells, which is required for the proper progression through mitosis. Previously, we showed that treatment of human prostate cancer cells with 2-methoxyestradiol (2-ME) or docetaxel results in an accumulation of cyclin B1 protein and an increase in cyclin B1 kinase activity, followed by induction of apoptotic cell death. Inhibition of cyclin B1 kinase lowers apoptosis induced by 2-ME and docetaxel. In this study, we established a positive correlation between cyclin B1 protein and apoptosis induced by chemotherapy in prostate cancer cells. There is minimal cyclin B1 and induction of apoptosis by chemotherapy in nontransformed cells. LNCaP and PC-3 prostate cancer cells stably overexpressing cyclin B1 are more sensitive to apoptosis induced by chemotherapy. LNCaP cells expressing cyclin B1 small interfering RNA to lower cyclin B1 protein or dominant negative cyclin-dependent kinase 1 to inhibit cyclin B1 kinase show a decrease in apoptosis. Increased sensitivity to apoptosis by overexpression of cyclin B1 may be due to lower Bcl-2, higher p53, and decreased neuroendocrine differentiation. We suggest that a cancer-specific mechanism whereby 2-ME and docetaxel may exert anti-prostate cancer activity is the deregulated activation of cyclin B1 kinase, leading to the induction of apoptotic cell death. Our results also suggest that higher levels of cyclin B1 in prostate cancer cells may be a good prognostic marker for chemotherapy.
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PMID:Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy. 1751 2

Propolis is a resinous substance collected by bees (Apis mellifera) from various tree buds which they then use to coat hive parts and to seal cracks and crevices in the hive. Propolis, a known ancient folk medicine, has been extensively used in diet to improve health and to prevent disease. In the present study, we have evaluated the effects of ethanolic extracts of Brazilian propolis group l2 and bud resins of botanical origin (B. dracunculifolia), and propolis group 3 on proliferation of metastasis (DU145 and PC-3) and primary malignant tumor (RC58T/h/SA#4)-derived human prostate cancer cells. The strongest inhibition was observed in propolis group 3 (sample #3) extracts whereas moderate growth inhibition was observed in human prostate epithelial cells. In the RC58T/h/SA#4 cells, resins of botanical origin of propolis group 12 (sample #1) and propolis group 12 (sample #2) induced growth inhibition that was associated with S phase arrest whereas propolis group 3 (sample #3) induced growth inhibition that was associated with G2 arrest. The mechanisms of cell cycle effects of propolis were investigated. The resins of botanical origin of propolis group 12 and propolis group 12 showed similar inhibition of cyclin D1, CDK4 and cyclin B1 expression. Propolis group 3 showed higher induction of p21 expression but no inhibition of cyclin D1, CDK4 and cyclin B1 expression. The results obtained here demonstrate that the Brazilian propolis extracts have significant inhibitory effect on proliferation of human prostate cancer cells. Inhibition was achieved through regulation of protein expression of cyclin D1, B1 and cyclin dependent kinase (CDK) as well as p21. Our results indicate that the Brazilian propolis extracts show promise as chemotherapeutic agents as well as preventive agents against prostate cancer.
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PMID:Antiproliferation of human prostate cancer cells by ethanolic extracts of Brazilian propolis and its botanical origin. 1767 87

Insulin-like growth factor binding protein-3 (IGFBP-3), an antiproliferative and proapoptotic protein, has been shown to be upregulated by growth inhibitory concentrations of androgens in LNCaP human prostate cancer (PCa) cells, but the mechanism of regulation and the role of IGFBP-3 in the modulation of PCa cell proliferation are unknown. In this study, we have examined the effects of a range of concentrations of the synthetic androgen R1881 on IGFBP-3 expression and cell growth in LNCaP cells. We have also investigated the role of androgen-stimulated IGFBP-3 in androgen-induced growth inhibition. We show that low doses of R1881 stimulate LNCaP cell proliferation, but do not induce IGFBP-3 expression, whereas high doses of R1881 that inhibit cell growth, significantly increase expression of IGFBP-3. Importantly, we demonstrate that the combination of calcitriol and androgens not only synergistically upregulates IGFBP-3 expression but also inhibits cell growth better than either hormone alone. siRNA knockdown of IGFBP-3 expression partially reverses the growth inhibition by calcitriol and by androgens. Furthermore, we find that the growth inhibitory dose of R1881 leads to increases in the cyclin dependent kinase inhibitors (CDKIs), p21 and p27 as well as to G1 arrest. These changes can be blocked or partially reversed by IGFBP-3 siRNA, indicating that the induction of CDKIs is downstream of IGFBP-3. Our data suggest, for the first time, that IGFBP-3 is involved in the antiproliferative action of high doses of androgens partly through p21 and p27 pathways and that IGFBP-3 may contribute significantly to androgen-induced changes in LNCaP cell growth.
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PMID:The role of insulin-like growth factor binding protein-3 in the growth inhibitory actions of androgens in LNCaP human prostate cancer cells. 1791 55

Histone deacetylase (HDAC) inhibitors have been shown to modify the expression of a variety of genes related to cell cycle regulation and apoptosis in several cancer cells. However, the precise mode of action of HDAC inhibitors in prostate cancer cells is not completely understood. This study examined whether an HDAC inhibitor affects cell death in human prostate cancer cells through the epigenetic regulation of androgen receptor (AR) expression. The molecular mechanism of the HDAC inhibitor, sodium butyrate, on the epigenetic alterations of cell cycle regulators was evaluated in androgen-dependent human prostate cancer LNCaP cells. The expression levels of acetylated histone H3 and H4 increased significantly after 48 h treatment with sodium butyrate. Sodium butyrate induced the expression of AR after 48 h treatment. In addition, immunofluorescence assay revealed the nuclear localization of the AR after sodium butyrate treatment. Sodium butyrate also significantly decreased the expression of the cell cycle regulatory proteins (cyclin D1/cyclin dependent kinase (CDK)4, CDK6, and cyclin E/CDK2) in the LNCaP cells after 48 h treatment. Furthermore, p21Waf1/Cip1 and p27Kip1 were upregulated as a result of the sodium butyrate treatment. These results suggest that sodium butyrate effectively inhibited cell proliferation and induced apoptosis of human prostate cancer cells by altering the expression of cell cycle regulators and AR. This study indicated that sodium butyrate may be a potential agent in prostate cancer treatment.
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PMID:Sodium butyrate regulates androgen receptor expression and cell cycle arrest in human prostate cancer cells. 1797 72

The forkhead box O (FOXO) transcription factor FOXO1 functions as a tumor suppressor by regulating expression of genes involved in apoptosis, cell cycle arrest and oxidative detoxification. Here, we demonstrate that cyclin-dependent kinase 1 (CDK1) specifically phosphorylates FOXO1 at serine 249 (S249) in vitro and in vivo. Coimmunoprecipitation assays demonstrate that both endogenous CDK1 and ectopically expressed CDK1 form a protein complex with FOXO1 in prostate cancer (PCa) cells. In vitro protein binding assays reveal that CDK1 interacts directly with FOXO1. Accordingly, overexpression of CDK1 inhibits the transcriptional activity of FOXO1 in PCa cells through S249 phosphorylation on FOXO1. Consistent with the roles of FOXO3a and FOXO4 (two other members of the FOXO family) in cell cycle regulation, forced expression of FOXO1 causes a delay in the transition from G2 to M phase. This effect is blocked completely by overexpression of CDK1 and cyclin B1. Ectopic expression of constitutively active CDK1 also inhibits FOXO1-induced apoptosis in PCa cells. Moreover, we demonstrate that the inhibitory effect of FOXO1 on Ras oncogene-induced colony formation in fibroblasts is diminished by overexpression of CDK1. Given that CDK1 and cyclin B1 are often overexpressed in human cancers including PCa, our findings suggest that aberrant activation of CDK1 may contribute to tumorigenesis by promoting cell proliferation and survival via phosphorylation and inhibition of FOXO1.
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PMID:CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. 1840 65

Roles of cyclin dependent kinase inhibitors, p21/Cip1 (p21) and p27/Kip1 (p27) in prostate cancer (PCa) progression is still not clear. Lower p27 protein expression in PCa tissues is often associated with poor prognosis, but prognostic significance of p21 is still controversial. Herein, we investigated the role of these molecules in determining PCa growth characteristics. We generated human PCa DU145 cell variants with knocked down levels of p21 (DU-p21) or p27 (DU-p27), or both (DUp21 + p27) via retroviral transduction of respective shRNAs and compared their various characteristics with empty vector-transduced DU145 (DU-EV) cells in vitro as well as in vivo. Knocking down either p21 or p27 did not show any significant change in doubling time, clonogenicity and cell cycle progression in DU145 cells, but simultaneous knock-down of both p21 and p27 significantly enhanced these parameters. In athymic mice, DU-p21 + p27 tumors showed higher growth rate than the comparable growth of DU-EV, DU-p21 and DU-p27 tumors. Concurrently, DU-p21 + p27 tumors had significantly higher proliferation rate, showing 54% and 48% increase in proliferating cell nuclear antigen (PCNA) and Ki-67-positive cells, respectively, compared to DU-EV tumors. DU-p21 + p27 tumors also showed higher microvessel density and increased expression of vascular endothelial growth factor (VEGF). Proliferation and angiogenic status of DU-p21 and DU-p27 tumors was comparable to DU-EV tumors. Both in vitro and in vivo results implicate that p21 and p27 have compensatory roles in advanced prostate cancer cells, and ablation or downmodulation of both these molecules essentially enhances the aggressive prostate carcinoma phenotype.
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PMID:Downregulation of both p21/Cip1 and p27/Kip1 produces a more aggressive prostate cancer phenotype. 1858 41


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