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)

The present study was undertaken to gain insights into the mechanism of cell cycle arrest caused by honokiol, a constituent of oriental herb Magnolia officinalis. The honokiol treatment decreased the viability of PC-3 and LNCaP human prostate cancer cells in a concentration- and time-dependent manner, which correlated with G0-G1 phase cell cycle arrest. The honokiol-mediated cell cycle arrest was associated with a decrease in protein levels of cyclin D1, cyclin-dependent kinase 4 (Cdk4), Cdk6, and/or cyclin E and suppression of complex formation between cyclin D1 and Cdk4 as revealed by immunoprecipitation using anti-cyclin D1 antibody followed by immunoblotting for Cdk4 protein. The honokiol-treated PC-3 and LNCaP cells exhibited a marked decrease in the levels of total and phosphorylated retinoblastoma protein (Rb), which correlated with the suppression of transcriptional activity of E2F1. Exposure of PC-3 and LNCaP cells to honokiol resulted in the induction of p21 (PC-3 and LNCaP) and p53 protein expression (LNCaP). However, small interfering RNA (siRNA)-mediated knockdown of either p21 (PC-3 and LNCaP) or p53 (LNCaP) protein failed to confer any protection against honokiol-induced cell cycle arrest. The honokiol treatment caused the generation of reactive oxygen species (ROS), and the cell cycle arrest caused by honokiol was partially but significantly attenuated in the presence of antioxidant N-acetylcysteine. In conclusion, the present study reveals that the honokiol-mediated G0-G1 phase cell cycle arrest in human prostate cancer cells is associated with the suppression of protein level/phosphorylation of Rb leading to inhibition of transcriptional activity of E2F1.
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PMID:Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity. 1793 62

We have recently shown that curcumin induces apoptosis in prostate cancer cells through Bax translocation to mitochondria and caspase activation, and enhances the therapeutic potential of TRAIL. However, the molecular mechanisms by which it causes growth arrest are not well-understood. We studied the molecular mechanism of curcumin-induced cell cycle arrest in prostate cancer androgen-sensitive LNCaP and androgen-insensitive PC-3 cells. Treatment of both cell lines with curcumin resulted in cell cycle arrest at G1/S phase and that this cell cycle arrest is followed by the induction of apoptosis. Curcumin induced the expression of cyclin-dependent kinase (CDK) inhibitors p16(/INK4a), p21(/WAF1/CIP1) and p27(/KIP1), and inhibited the expression of cyclin E and cyclin D1, and hyperphosphorylation of retinoblastoma (Rb) protein. Lactacystin, an inhibitor of 26 proteasome, blocks curcumin-induced down-regulation of cyclin D1 and cyclin E proteins, suggesting their regulation at level of posttranslation. The suppression of cyclin D1 and cyclin E by curcumin may inhibit CDK-mediated phosphorylation of pRb protein. The inhibition of p21(/WAF1/CIP1) by siRNA blocks curcumin-induced apoptosis, thus establishing a link between cell cycle and apoptosis. These effects of curcumin result in the proliferation arrest and disruption of cell cycle control leading to apoptosis. Our study suggests that curcumin can be developed as a chemopreventive agent for human prostate cancer.
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PMID:Linkage of curcumin-induced cell cycle arrest and apoptosis by cyclin-dependent kinase inhibitor p21(/WAF1/CIP1). 1815 3

Stress-induced activation and metabolism of plasma membrane sphingolipids results in intracellular ceramide accumulation and has been shown to induce apoptosis in human prostate cancer cells. This effect has been observed using synthetic ceramide analogs, such as C6-ceramide; however, the effects of naturally-occurring sphingolipids, such as C18-ceramide and sphingomyelin (CerPCho), on apoptosis and prostate cancer cell proliferation have not been examined. The results of the present study demonstrate that natural (CerPCho, C18-ceramide) and synthetic (C6-ceramide) sphingolipids reduced PC-3 cell proliferation by 15 +/- 1.8, 17 +/- 2.5, and 46 +/- 2.1%, respectively (P < 0.05). These reductions in proliferation were due, in part, to increased cellular apoptosis. Treatment of PC-3 cells with CerPCho and C18-ceramide significantly increased apoptosis by 3.0 +/- 0.8 and 3.6 +/- 0.6%, respectively, compared to the untreated control, while the synthetic C6-ceramide significantly increased apoptosis by 55.7 +/- 0.4%. C6-ceramide-induced apoptosis was associated with cell cycle arrest in the G(2)/M phase, decreased extracellular signal-regulated kinase (ERK1/2) signaling and activation of the cell cycle regulatory protein, retinoblastoma (pRb). Treatment of PC-3 cells with C18-ceramide and CerPCho did not alter cell cycle distribution, pRb or ERK1/2 activation. Taken together, these results suggest that natural and synthetic sphingolipids induce apoptosis in PC-3 cells via distinct signaling mechanisms and potencies.
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PMID:Apoptotic effects of dietary and synthetic sphingolipids in androgen-independent (PC-3) prostate cancer cells. 1818 32

Arctiin is a major lignan constituent of Arctium lappa and has anti-cancer properties in animal models. It was recently reported that arctiin induces growth inhibition in human prostate cancer PC-3 cells. However, the growth inhibitory mechanism of arctiin remains unknown. Herein we report that arctiin induces growth inhibition and dephosphorylates the tumor-suppressor retinoblastoma protein in human immortalized keratinocyte HaCaT cells. We also show that the growth inhibition caused by arctiin is associated with the down-regulation of cyclin D1 protein expression. Furthermore, the arctiin-induced suppression of cyclin D1 protein expression occurs in various types of human tumor cells, including osteosarcoma, lung, colorectal, cervical and breast cancer, melanoma, transformed renal cells and prostate cancer. Depletion of the cyclin D1 protein using small interfering RNA-rendered human breast cancer MCF-7 cells insensitive to the growth inhibitory effects of arctiin, implicates cyclin D1 as an important target of arctiin. Taken together, these results suggest that arctiin down-regulates cyclin D1 protein expression and that this at least partially contributes to the anti-proliferative effect of arctiin.
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PMID:Arctiin induces cell growth inhibition through the down-regulation of cyclin D1 expression. 1828 7

The androgen receptor (AR) is a critical effector of prostate cancer development and progression. The dependence of this tumor type on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function (achieved either through ligand depletion and/or the use of AR antagonists) is the first line of therapeutic intervention. These strategies are initially effective, and induce a mixed response of cell cycle arrest or apoptosis in prostate cancer cells. However, recurrent, incurable tumors ultimately arise as a result of inappropriately restored AR function. Based on these observations, it is imperative to define the mechanisms by which AR controls cancer cell proliferation. Mechanistic investigation has revealed that AR acts as a master regulator of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent kinase (CDK) activity, induce phosphorylation/inactivation of the retinoblastoma tumor suppressor (RB), and thereby govern androgen-dependent proliferation. These functions appear to be independent of the recently identified TMPRSS2-ETS fusions. Once engaged, several components of the cell cycle machinery actively modulate AR activity throughout the cell cycle, thus indicating that crosstalk between the AR and cell cycle pathways likely modulate the mitogenic response to androgen. As will be discussed, discrete aberrations in this process can alter the proliferative response to androgen, and potentially subvert hormonal control of tumor progression.
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PMID:AR, the cell cycle, and prostate cancer. 1830 81

Telomere attrition, DNA damage and constitutive mitogenic signaling can all trigger cellular senescence in normal cells and serve as a defense against tumor progression. Cancer cells may circumvent this cellular defense by acquiring genetic mutations in checkpoint proteins responsible for regulating permanent cell cycle arrest. A small family of tumor suppressor genes encoding the retinoblastoma susceptibility protein family (Rb, p107, p130) exerts a partially redundant control of entry into S phase of DNA replication and cellular proliferation. Here we report that activation of the p53-dependent DNA damage response has been found to accelerate senescence in human prostate cancer cells lacking a functional Rb protein. This novel form of irradiation-induced premature cellular senescence reinforces the notion that other Rb family members may compensate for loss of Rb protein in the DNA damage response pathway. Consistent with this hypothesis, depletion of p107 potently inhibits the irradiation-induced senescence observed in DU145 cells. In contrast, p130 depletion triggers a robust and unexpected form of premature senescence in unirradiated cells. The dominant effect of depleting both p107 and p130, in the absence of Rb, was a complete blockade of irradiation-induced cellular senescence. Onset of the p107-dependent senescence was temporally associated with p53-mediated stabilization of the cyclin-dependent kinase inhibitor p27 and decreases in c-myc and cks1 expression. These results indicate that p107 is required for initiation of accelerated cellular senescence in the absence of Rb and introduces the concept that p130 may be required to prevent the onset of terminal growth arrest in unstimulated prostate cancer cells lacking a functional Rb allele.
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PMID:Distinct roles for p107 and p130 in Rb-independent cellular senescence. 1841 57

Androgen receptor plays a critical role in the development and maintenance of cancers in the prostate. Earlier, we have shown that Cdc6, a regulatory protein for initiation of DNA replication, is down regulated in androgen-insensitive prostate cancer cells. In this report, we studied the involvement of androgen, mediated through androgen receptor (AR) in regulation of Cdc6 expression. Our results demonstrated that androgen treatment stimulated Cdc6 expression in xenograft tumors and androgen-sensitive prostate cancer cells. We also showed that androgen treatment stimulated Cdc6 transcription through possible interaction of AR with the ARE sequence in the Cdc6 promoter and that the stimulatory effect of androgen required intact E2F binding sites in the promoter. Androgen treatment differentially altered nuclear availability of E2F1 and E2F3, and increased the amount of hypophosphorylated retinoblastoma protein (pRb) in the nucleus in a time dependent fashion. We further showed that AR interacted with E2F transcription factors in a ligand-independent manner and that ligand-bound AR was less efficient in interacting with E2F proteins. DNA-protein interaction assays indicated that androgen treatment altered binding of E2F1 to the Cdc6 promoter in prostate cancer cells. We conclude that AR regulates Cdc6 transcription through interaction with the Cdc6 promoter, and complex formation with E2F1 and E2F3 in a differential manner.
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PMID:Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells. 1854 Nov 54

Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain the peptide 'degron' from hypoxia-inducible factor-1alpha, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ERalpha; Protac-B). We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Treatment of estrogen-dependent breast cancer cells with Protac-B induced the degradation of ERalpha in a proteasome-dependent manner. Protac-B inhibited the proliferation of ERalpha-dependent breast cancer cells by inducing G(1) arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERalpha expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells induced G(1) arrest but did not affect cells that do not express AR. Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERalpha and AR, respectively.
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PMID:Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. 1879 99

Thiazolidinediones (TZDs) are peroxisome proliferator activated receptor gamma (PPARgamma) ligands that have been reported to reduce proliferation of human prostate cancer cells. However, the mechanisms by which TZDs inhibit prostate cancer cell proliferation are not fully understood. In addition, it is not known if the anti-proliferative effects of TZDs require activation of PPARgamma or are mediated by PPARgamma-independent pathways. The goals of this study were to assess whether TZDs regulate expression of proteins that control the transition from G1 to S phase of the cell cycle and define the role of PPARgamma in these TZD-induced responses in androgen-independent human prostate cancer cell lines. Western blot analysis revealed that growth inhibitory concentrations of the TZDs rosiglitazone and ciglitazone induced expression of the cyclin dependent kinase inhibitor p21 and decreased cyclin D1 levels in the androgen independent PC-3 cell line. Phosphorylation of retinoblastoma protein at Serine 780 was also reduced in PC-3 cells exposed to ciglitazone. Furthermore, growth inhibitory concentrations of ciglitazone increased p21 and lowered cyclin D1 expression within C4-2 cells. PPARgamma-directed siRNAs inhibited the ability of rosiglitazone to regulate expression of cyclin D1 and p21. However, knockdown of PPARgamma did not significantly reduce ciglitazone-induced alterations in cyclin D1 and p21. Furthermore PPARgamma siRNA did not prevent inhibition of PC-3 cell proliferation by either TZD. Thus, activation of PPARgamma is involved in rosiglitazone-induced alterations in cell cycle protein expression. However, the alterations in protein expression and proliferation induced by ciglitazone occur primarily via PPARgamma-independent signaling pathways.
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PMID:Thiazolidinediones regulate expression of cell cycle proteins in human prostate cancer cells via PPARgamma-dependent and PPARgamma-independent pathways. 1916 38

Galectin-3, a beta-galactoside-binding protein, has been implicated in a variety of biological functions including cell proliferation, apoptosis, angiogenesis, tumor progression, and metastasis. The present study was undertaken to understand the role of galectin-3 in the progression of prostate cancer. Immunohistochemical analysis of galectin-3 expression revealed that galectin-3 was cleaved during the progression of prostate cancer. Galectin-3 knockdown by small interfering RNA (siRNA) was associated with reduced cell migration, invasion, cell proliferation, anchorage-independent colony formation, and tumor growth in the prostates of nude mice. Galectin-3 knockdown in human prostate cancer PC3 cells led to cell-cycle arrest at G(1) phase, up-regulation of nuclear p21, and hypophosphorylation of the retinoblastoma tumor suppressor protein (pRb), with no effect on cyclin D1, cyclin E, cyclin-dependent kinases (CDK2 and CDK4), and p27 protein expression levels. The data obtained here implicate galectin-3 in prostate cancer progression and suggest that galectin-3 may serve as both a diagnostic marker and therapeutic target for future disease treatments.
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PMID:Regulation of prostate cancer progression by galectin-3. 1928 70


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