UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

25-Hydroxyvitamin D-1alpha-hydroxylase (lalpha-OHase) is expressed in prostate cells. The expression suggests that local production of 1,25-dihydroxyvitamin D could provide an important cell growth regulatory mechanism. However, there is differential expression of 1alpha-OHase activity among the primary cultures of prostate cells derived from cancerous, benign prostatic hypertrophy and normal tissue, and among noncancerous (PZHPV-7) and various cancer cell lines (PC-3, DU145). No activity was found in cancer cell line LNCaP. The observed marked decrease in 1alpha-OHase activity in prostate cancer cells suggests some defect of the 1alpha-OHase in these cells. Using luciferase reporter gene assay, we observed a step-wise decrease in the basal promoter activity in two truncated promoter fragments, AN2 (-1,100 bp) and AN5 (-394 bp), with the highest basal activities found in PZHPV-7 and with loss of promoter activity in LNCaP. In order to understand the mechanism underlying the differential promoter activities among different prostate cells, we investigated the possible role of phosphorylation of cyclic AMP response element binding protein (CREB) on the regulation of 1alpha-OHase promoter activity in the four prostate cell lines. First we compared the levels of CREB phosphorylation among PZHPV-7, DU145, PC-3 and LNCaP cells by Western blot analysis using antibody against phosphorylated CREB. We observed that CREB was phosphorylated to a greater extent in PZHPV-7 than in DU145 cells. No significant phosphorylation of CREB was found in PC-3 and LNCaP cells. Next, we utilized activators and inhibitors of protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase kinase (MAPKK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to determine which kinases might be involved in phosphorylating the CREB in PZHPV-7 cells. We demonstrated that forskolin (an activator of PKA) increased the AN2 basal promoter activity 50%, whereas H-89 (an inhibitor of PKA) inhibited the basal and forskolin-stimulated AN2 promoter activity 40% and 70%, respectively. We also showed that PD98059 (an inhibitor of MAPKK) decreased the AN2 promoter activity 70%. Phorbol 12-myristate 13-acetate (an activator of PKC), GF109203 (an inhibitor of PKC) and KN-93 (an inhibitor of CaMKII) had no effect on AN2 promoter activity in PZHPV-7 cells. Thus, our results suggest that differential phosphorylation of CREB through PKA and MAPK pathways may be involved in the regulation of 1alpha-OHase promoter activity.
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PMID:Vitamin D autocrine system and prostate cancer. 1289 25

Cdc37 is a co-chaperone protein that recruits several immature client kinases to Hsp90 for proper folding. Cdc37 up-regulation is a common early event in localized human prostate cancer. Although targeted overexpression in mice leads to prostate epithelial cell hyperplasia, the effect of Cdc37 dysregulation in human prostate cells is unclear. In this study, we examine the role of Cdc37 in the growth regulation of normal prostate epithelial cells using a unique human model system. We demonstrate that Cdc37 overexpression drives proliferation, whereas loss of Cdc37 function arrests growth and leads to apoptosis. With increased Cdc37 expression, molecular analysis of Cdc37 client pathways demonstrates enhanced Raf-1 activity, greater Cdk4 levels, and reduced expression of the cyclin-dependent kinase inhibitor p16/CDKN2. To further investigate these downstream pathways, enhanced Raf-1 or Cdk4 activities were selectively induced in human prostate epithelial cells. Raf-1 activation inhibited proliferation and generated an enlarged, flattened morphology. Induction of Cdk4 activity using cyclin D1 overexpression, however, was sufficient to promote proliferation. These data indicate that Cdc37 induces proliferation and is critical for survival in human prostate epithelial cells. These alterations in cell division and survival may be important in the development and progression of early prostate cancer.
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PMID:Cdc37 enhances proliferation and is necessary for normal human prostate epithelial cell survival. 1290 40

To investigate whether the tumor suppressor gene PTEN affects the activity of the androgen receptor (AR), we monitored the expression of the apoptotic gene HA-Bax (inserted in an adenovirus where it is driven by the AR-responsive promoter ARR(2)PB) in the presence or absence of dihydrotestosterone, in PTEN (+) or (-) prostate cancer cell lines, infected with an adenovirus containing wild-type PTEN (Av-CMV-PTEN) or a control LacZ-expressing construct. Our results showed that AR transcriptional activity was antagonized by PTEN expression. This antagonism was not cell line dependent, as it was observed in both LNCaP and LAPC-4 cells, or promoter dependent, as it was observed for a reporter gene (HA-Bax) driven by an exogenous androgen-responsive promoter (the ARR(2)PB promoter), and for a native gene (prostate-specific antigen; PSA) driven by an endogenous AR-responsive promoter. Additional experiments performed with viruses containing constitutively active (Adeno-myrAkt) or dominant negative (Adeno-dnAkt) forms of Akt demonstrated that Akt, a protein kinase whose activation is known to be inhibited by PTEN, mediated the observed antagonism between PTEN and AR transcriptional activity. Recently, two putative Akt phosphorylation sites have been identified in the AR sequence. Site-directed mutagenesis was utilized to convert these two serine into alanine residues. The resulting construct, named CMV-AR S213A&S791A was transfected in AR (-) and PTEN (-) PC-3 cells in the presence or absence of Av-CMV-PTEN and of two reporter plasmids (GRE(2)E1b-Luc and PSA P/E-luc) containing the luciferase gene driven by well-characterized androgen responsive promoters. These experiments demonstrated that, similarly to the wild-type molecule, AR S213A&S791A was transcriptionally inhibited by PTEN, suggesting that Akt does not have an effect on AR transcription by direct phosphorylation, but probably by affecting the availability of a downstream molecule whose main mechanism of action is that of modulating AR transcription. The data presented here suggest that loss of PTEN function may facilitate activation of AR signaling and progression to androgen independence in prostate cancer.
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PMID:The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity. 1291 34

Epidemiological studies recently concluded that consumption of cruciferous vegetables such as broccoli, cabbage, and cauliflower, etc. is inversely related to prostate cancer risk, although the mechanism of prevention and the responsible phytochemicals are unknown. Since clinically significant prostate cancer eventually can grow independent of androgen, the association of the growth and tumorigenesis of such prostate cancer cells with sulforaphane (SFN) which is a predominant isothiocyanate in cruciferous vegetables, investigated. These vegetables contain high concentrations of glucosinolate glucoraphanin, which yield sulforaphane when hydrolyzed by the plant enzyme myrosinase. This study showed that exposure of human androgen-independent DU-145 prostate cancer cells to SFN resulted in the inhibition of growth and tumorigenesis, as revealed by a reduction in cell density, DNA synthesis, and clonogenesis. Analyses of the mechanism revealed that SFN mediated cell cycle arrest by modulating the expression and functions of cell cycle regulators. SFN induced signals that inhibited the activity of cyclin-dependent kinase cdk4 with an up-stream induction of cdk inhibitor p21WAF-1/Cip-1, and reduced cyclin D1. The inhibition of cdk kinase activity could be affected with <1 micro M SFN within 24 h. As a result, phosphorylation of Rb proteins, which activates the transition from G1- to S-phase, was significantly decreased and the cell cycle progression retarded. SFN also down-regulated the expression of bcl-2, a suppressor of apoptosis, and activated caspases to execute apoptosis in the prostate cancer cells. The regulators of cell cycle have thus been revealed as targets of sulforaphane for growth arrest and apoptosis induction. The potential of SFN, as an active dietary factor to inhibit initiation and post-initiation of prostate cancer carcinogenesis is discussed.
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PMID:Targeting cell cycle machinery as a molecular mechanism of sulforaphane in prostate cancer prevention. 1465 56

The oncogene Bcl-2 is upregulated frequently in prostate tumors following androgen ablation therapy, and Bcl-2 overexpression may contribute to the androgen-refractory relapse of the disease. However, the molecular mechanism underlying androgenic regulation of Bcl-2 in prostate cancer cells is understood poorly. In this study, we demonstrated that no androgen response element (ARE) was identified in the androgen-regulated region of the P1 promoter of Bcl-2 gene, whereas, we provided evidence that the androgenic effect is mediated by E2F1 protein through a putative E2F-binding site in the promoter. We further demonstrated that retinoblastoma (RB) protein plays a critical role in androgen regulation of Bcl-2. The phosphorylation levels of RB at serine residues 780 and 795 were decreased in LNCaP cells treated with androgens. Ectopic expression of a constitutively active form of RB inhibited expression of Bcl-2. Knockdown of endogenous RB protein by an Rb small inference RNA (siRNA) induced an increase in Bcl-2 levels. Most importantly, the effect of androgens on Bcl-2 was abolished completely by specific inhibition of RB function with a mutated E1A. Finally, androgen treatment of LNCaP cells upregulated specifically levels of the cyclin-dependent kinase inhibitors (CDKIs) p15INK4B and p27KIP1. Ectopic expression of p15INK4B and/or p27KIP1 inhibited Bcl-2 expression. Knockdown of endogenous p15INK4B or p27KIP1 protein with a pool of siRNAs diminished androgen-induced downregulation of Bcl-2 expression. Therefore, our data indicate that androgens suppress Bcl-2 expression through negatively modulating activities of the E2F site in the Bcl-2 promoter by activating the CDKI-RB axis.
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PMID:Androgens repress Bcl-2 expression via activation of the retinoblastoma (RB) protein in prostate cancer cells. 1467 36

Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), has often been implicated in prostate cancer. Studies in prostate tumor cell lines revealed that Akt activation is probably important for the progression of prostate cancer to an androgen-independent state. Investigations of human prostate cancer tissues show that although there is neither Akt gene amplification nor enhanced protein expression in prostate cancer compared to normal tissue, poorly differentiated tumors exhibit increased expression of a phosphorylated (activated) form of Akt compared to normal tissue, prostatic intraepithelial neoplasia (PIN) or well-differentiated prostate cancer. Akt phosphorylation is accompanied by the inactivation of ERK, a member of the mitogen activated protein kinase (MAPK) family. In this article, we postulate that Akt promotes androgen-independent survival of prostate tumor cells by modulating the expression and activation of the androgen receptor (AR).
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PMID:Akt in prostate cancer: possible role in androgen-independence. 1468 76

The alpha2-macroglobulin signalling receptor is upregulated in highly metastatic 1-LN prostate cancer cells. Stimulation of 1-LN cells with activated alpha2-macroglobulin (alpha2M*) caused a two- to threefold increase in [3H]thymidine uptake and cell number. These events require the Ras-dependent MAPK and PI 3-kinase/Akt signalling cascades. Incubation of 1-LN cells with alpha2M* induced Grb2, shc, sos and Raf-1 expression, as well as phosphorylation of MEK 1/2, ERK 1/2, p38 MAPK and JNK. This treatment also increased PI 3-kinase activation, PDK1 expression, Akt phosphorylation and p70s6k phosphorylation. Levels of the early gene products c-fos protein and thymidylate synthase were comparably increased. Exposure of 1-LN cells to alpha2M* significantly raised the levels of phosphorylated CREB by about 15-20 min and phosphorylated p53 by about 60-90 min of incubation. We conclude that the growth regulatory effects of ligating the alpha2M* signalling receptor on 1-LN cells are exerted via the onset and crosstalk between the Ras-dependent MAPK and PI 3-kinase/Akt signalling cascades.
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PMID:Potentiation of signal transduction mitogenesis and cellular proliferation upon binding of receptor-recognized forms of alpha2-macroglobulin to 1-LN prostate cancer cells. 1470 37

Antisense oligonucleotides (ASONs) are one of the new classes of molecularly targeted agents that have transitioned from the laboratory into clinical trials. Rational drug design has resulted in agents directed against a number of important cellular targets, including the mRNA of bcl-2, protein kinase (PK) C-alpha, PKA-I, H-ras, c-raf, R1 and R2 subunit of ribonucleotide reductase, and transforming growth factor beta2. These drugs are well tolerated with favorable toxicity profiles, and preliminary studies have demonstrated that they can be feasibly combined with chemotherapy. Plasma half-life is short, generally necessitating continuous prolonged intravenous infusion. Shorter administration schedules are being investigated. Efficacy has been demonstrated in early-phase studies in non-small-cell lung cancer (NSCLC), non-Hodgkin's lymphoma, ovarian cancer, melanoma, and prostate cancer. Molecular correlative studies with peripheral blood mononuclear cells and tumor tissue have demonstrated suppression of target proteins, suggesting that these drugs are indeed reaching the target. Here we discuss the current status of development of ASONs, focusing on LY900003 (formerly ISIS 3521), an agent directed against PKC-alpha currently under study in NSCLC. Phase III studies will determine the ultimate role these agents will play in the treatment of cancer. Future areas of study include combination with radiation and other molecularly targeted agents, alternative dosing schedules, liposomal administration, and the development of new antisense agents directed against additional molecular targets.
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PMID:Antisense oligonucleotides in the treatment of non-small-cell lung cancer. 1472 Mar 40

Development of effective agents for treatment of hormone-refractory prostate cancer has become a national medical priority. We have reported recently that apigenin (4',5,7-trihydroxyflavone), found in many common fruits and vegetables, has shown remarkable effects in inhibiting cell growth and inducing apoptosis in many human prostate carcinoma cells. Here we demonstrate the molecular mechanism of inhibitory action of apigenin on androgen-refractory human prostate carcinoma DU145 cells that have mutations in the tumor suppressor gene p53 and pRb. Treatment of cells with apigenin resulted in a dose- and time-dependent inhibition of growth, colony formation, and G1 phase arrest of the cell cycle. This effect was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner, cyclin-dependent kinase (cdk)2, 4, and 6, with concomitant upregulation of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18. The induction of WAF1/p21 and its growth inhibitory effects by apigenin appears to be independent of p53 and pRb status of these cells. Apigenin treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1 (Apaf-1). This effect was found to result in a significant increase in cleaved fragments of caspase-9, -3, and poly(ADP-ribose) polymerase (PARP). Further, apigenin treatment resulted in downmodulation of the constitutive expression of nuclear factor-kappaB (NF-kappaB)/p65 and NF-kappaB/p50 in the nuclear fraction that correlated with an increase in the expression of IkappaB-alpha (IkappaBalpha) in the cytosol. Taken together, we concluded that molecular mechanisms during apigenin-mediated growth inhibition and induction of apoptosis in DU145 cells was due to (1) modulation in cell-cycle machinery, (2) disruption of mitochondrial function, and (3) NF-kappaB inhibition.
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PMID:Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. 1475 Feb 16

The Src-related protein kinase Lyn plays an important role in B-cell activation. However, several lines of evidence suggest that it is also involved in the control of cellular proliferation and the inhibition of apoptosis. We have discovered that Lyn is expressed in normal prostate epithelia, in 95% of primary human prostate cancer (PC) specimens examined, and in all of the PC cell lines that we assayed. Moreover, Lyn knockout mice display abnormal prostate gland morphogenesis, which suggests that Lyn plays an important role in prostate epithelium development and implies that Lyn is a candidate target for specific therapy for PC. Using a drug-design strategy to construct sequence-based peptide inhibitors, a Lyn-specific inhibitor, KRX-123, targeting a unique interaction site within Lyn, was synthesized. KRX-123 was found to inhibit cellular proliferation in three hormone-refractory PC cell lines, DU145, PC3, and TSU-Pr1 with IC(50) values of 2-4 micro M. In vivo, tumor volume of DU145 explants in nude mice was significantly reduced after once-a-week injections of KRX-123, at a dose of 10 mg/kg, for a period of 5 weeks. Histological analyses of the treated tumors indicated extensive apoptosis. Thus, we suggest that Lyn inhibition may serve as a prime target for the treatment of hormone-refractory PC.
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PMID:Lyn is a target gene for prostate cancer: sequence-based inhibition induces regression of human tumor xenografts. 1487 38

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