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)

Androgen-ablation is a most commonly prescribed treatment for metastatic prostate cancer but it is not curative. Development of new strategies for treatment of prostate cancer is limited partly by a lack of full understanding of the mechanism by which androgen regulates prostate cancer cell proliferation. This is due, mainly, to the limitations in currently available experimental models to distinguish androgen/androgen receptor (AR)-induced events specific to proliferation from those that are required for cell viability. We have, therefore, developed an experimental model system in which both androgen-sensitive (LNCaP) and androgen-independent (DU145) prostate cancer cells can be reversibly blocked in G(0)/G(1) phase of cell cycle by isoleucine deprivation without affecting their viability. Pulse-labeling studies with (3)H-thymidine indicated that isoleucine-deprivation caused LNCaP and DU145 cells to arrest at a point in G(1) phase which is 12-15 and 6-8 h, respectively, before the start of S phase and that their progression into S phase was dependent on serum factors. Furthermore, LNCaP, but not DU145, cells required AR activity for progression from G(1) into S phase. Western blot analysis of the cell extracts prepared at regular intervals following release from isoleucine-block revealed remarkable differences in the expression of cyclin E, p21(Cip1), p27(Kip1), and Rb at the protein level between LNCaP and DU145 cells during progression from G(1) into S phase. However, in both cell types Cdk-2 activity associated with cyclin E and cyclin A showed an increase only when the cells transited from G(1) into S phase. These observations were further corroborated by studies using exponentially growing cells that were enriched in specific phases of the cell cycle by centrifugal elutriation. These studies demonstrate usefulness of the isoleucine-deprivation method for synchronization of androgen-sensitive and androgen-independent prostate cancer cells, and for examining the role of androgen and AR in progression of androgen-sensitive prostate cancer cells from G(1) into S phase.
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PMID:Synchronized prostate cancer cells for studying androgen regulated events in cell cycle progression from G1 into S phase. 1270 43

Mevastatin arrested HCT116 colon cancer cells at the G1/S transition and increased cellular levels of p21CIP1/WAF1. p21-deficient colon cancer cells continued to proliferate in the presence of mevastatin. Although p21 was necessary for the G1/S block, the G1 cyclin-dependent kinases (Cdks) cyclin E-Cdk2 and cyclin D-Cdk4 remained active. Despite the activity of the G1 Cdks the retinoblastoma protein was hypophosphorylated due to unknown mechanisms that were dependent on the p21 protein. The resulting decrease in cyclin A mRNA and protein led to a decrease in the activity of cyclin A-Cdk2. Therefore, although p21 was required for the G1/S arrest of HCT116 colon cancer cells by mevastatin, its mode of action was more complicated than the simple formation of a physical complex with cyclin-Cdk2. This mechanism of inhibition is different from that seen in prostate cancer cells (Ukomadu, C., and Dutta, A. (2003) J. Biol. Chem. 278, 4840-4846) where the activating phosphorylation of cyclin E-Cdk2 is suppressed and p21 is not required, suggesting the existence of cell line-specific differences in the mechanism by which statins arrest the cell cycle.
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PMID:p21-dependent inhibition of colon cancer cell growth by mevastatin is independent of inhibition of G1 cyclin-dependent kinases. 1293 Aug 30

In the planning of future intervention trials using chemopreventive agents against lung cancer, it is critical to evaluate the effect on biomarkers implicated specifically in lung carcinogenesis. With the use of the H520 and H522 human lung cancer cell lines, the present study showed that treatment with selenium (in the form of methylseleninic acid) inhibited cell growth, arrested cell cycle progression at G(1), and induced apoptosis as a late event. Because H520 cells were more sensitive to selenium than H522 cells (IC(50) of MSA was 2.5 or 10 micro M for H520 or H522 cells, respectively, at 24 h), a panel of nine cell cycle regulatory proteins known to be involved in G(1)-->S transition was assessed by Western analysis using whole cell lysate from H520 cells. These nine proteins (DP1, cdc25A, cyclin A, cyclin B(1), cyclin D(1), cdk1, cdk5, p21(WAF1), and GADD153) have been reported previously by our laboratory to be modulated by MSA in human breast and prostate cancer cells. Our data showed that only four (DP1, cdc25A, p21(WAF1), and GADD153) of nine biomarkers produced the expected changes after treatment of lung cancer cells with MSA. This finding raises the possibility that the molecular targets sensitive to selenium modulation may be tissue specific. Thus, the selection of selenium biomarkers for evaluation in an intervention trial must be based on empirical data derived from the cancer cell type of interest.
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PMID:Cell cycle arrest biomarkers in human lung cancer cells after treatment with selenium in culture. 1465 89

Bone morphogenetic protein-2 (BMP-2), a multifunctional member of the transforming growth factor (TGF)-beta, superfamily, has powerful osteoinductive effects and causes cell cycle arrest in a variety of transformed cell lines. We have observed BMP-2-induced inhibition of cell proliferation in an androgen-dependent human prostate cancer cell line (LNCaP). To investigate the mechanism of inhibition of androgen-dependent growth by BMP-2, we examined the effect of dihydrotestosterone (DHT) and/or BMP-2 on cell cycle-related proteins in LNCaP cells. BMP-2 decreased the phosphorylation of retinoblastoma (Rb) protein induced by treatment with DHT. DHT-induced expression of cyclin A and cyclin-dependent kinase 2 (CDK2) protein was also inhibited by co-treatment with BMP-2. Furthermore, BMP-2 induced expression of p21(WAF1/CIP1), a CDK inhibitor. These results indicate that changes in expression of these proteins lead to modulation of the phosphorylation state of Rb. DHT-induced E2F-1 protein and mRNA expressions was also inhibited by BMP-2, suggesting that BMP-2 inhibits DHT-induced growth of LNCaP cells through a decrease in E2F protein expression and suppression of E2F activity by hypophosphorylation of Rb.
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PMID:Bone morphogenetic protein-2 induces hypophosphorylation of Rb protein and repression of E2F in androgen-treated LNCaP human prostate cancer cells. 1564 40

We have shown previously that androgen receptor (AR) activity is required for the progression of cells from G(1) to S phase. In an attempt to elucidate the mechanism of androgen- and androgen-receptor-mediated proliferation of prostate cancer cells, we studied the effect of anti-androgen bicalutamide (Casodex) on the expression of cell-cycle regulatory genes in synchronized LNCaP cells progressing from G(1) to S phase. LNCaP cells were synchronized by isoleucine-deprivation. Expression of cell-cycle regulatory genes in S phase control cells versus Casodex-treated cells that fail to enter S phase was studied using a microarray containing cDNA probes for 111 cell-cycle specific genes. RT-PCR and Western-blots were used to validate microarray data. Casodex blocked synchronized LNCaP cells from entering S phase. Microarrays revealed downregulation of eight genes in cells prevented from entering into S phase by Casodex. Of these eight genes, only Cdc6, cyclin A, and cyclin B were downregulated at both the mRNA and protein level in Casodex treated cells as compared to control cells. The mRNA and protein levels of Cdc6 increased as synchronized LNCaP cells progressed from G(1) to S phase, and were attenuated in Casodex-treated cells failed to enter S phase. Cyclins A and B were detected when cells entered S phase, but not when they were in G(1) phase. Like Cdc6, the levels of both cyclins A and B were attenuated in Casodex-treated cells. AR may play an important role in the onset of DNA synthesis in prostate cancer cells by regulating the expression and stability of Cdc6, which is critically required for the assembly of the pre-replication complex(pre-RC).
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PMID:Androgen receptor regulates Cdc6 in synchronized LNCaP cells progressing from G1 to S phase. 1588 48

Prostate cancer is the major health problem and the leading cause of male cancer death. Quercetin is a novel antitumor and antioxidant, whose molecular mechanism involved in cell cycle arrest in androgen independent prostate cancer cells remains unclear. In this study, we investigated the effects of quercetin on proliferation and cell cycle arrest by modulation of Cdc2/Cdk-1 protein in prostate cancer cells (PC-3). PC- 3 cells are human androgen independent cancer cells and were cultured with quercetin at concentrations of 50 and 100 microM for 24 h. Cell proliferation, apoptosis and cell cycle distribution were analyzed. Expression of Cdc2/Cdk-1, cyclin B1, cyclin A, p21/Cip1, pRb, pRb2/p130, Bcl-2, Bcl-X(L), Bax and caspase-3 proteins were studied with western blot analysis. Addition of quercetin led to substantial decrease in the expression of Cdc2/Cdk-1, cyclin B1 and phosphorylated pRb and increase in p21. Flowcytometric analysis showed that quercetin blocks G2-M transition, with significant induction of apoptosis. Apoptosis markers like Bcl-2 and Bcl-X(L) were significantly decreased and Bax and caspase-3 were increased. From this study, it was concluded that quercetin inhibits prostate cancer cell proliferation by altering the expression of cell cycle regulators and apoptotic proteins.
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PMID:Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. 1604 7

Basic research and clinical chemoprevention trials support the protective role of selenium in cancer prevention but the mechanisms based on the molecular level remain to be fully defined. This mini-review focuses only on the elucidation of the molecular mechanisms of cancer prevention by selenium using the genomics approach; target organs discussed here are breast, prostate, colon and lung. The results described here support the utility of microarray technology in delineating the molecular mechanisms of cancer prevention by selenium. These results are based on studies employing human and rodent cell lines and tissues from animal models ranging from normal to frank cancer. The dose and the form of selenium are determining factors in cancer chemoprevention. The results of the microarray analysis reviewed here indicate that selenium, independent of its form and the target organ examined, alters several genes in a manner that can account for cancer prevention. Selenium can up regulate genes related to phase II detoxification enzymes, certain selenium-binding proteins and select apoptotic genes, while down regulating those related to phase I activating enzymes and cell proliferation. Independent of tissue type, selenium arrests cells in G1 phase of cell cycle, inhibits CYCLIN A, CYCLIN D1, CDC25A, CDK4, PCNA and E2F gene expressions while induces the expressions of P19, P21, P53, GST, SOD, NQO1, GADD153 and certain CASPASES. In addition to those described above, genes such as OPN, which is mainly involved in metastasis and recently reported to be down regulated by selenium, should be considered as potential molecular marker in clinical chemoprevention trials. Collectively, literature data indicate that some of these genes that were altered by selenium are also involved in the development of human cancers described in this review. It appears that androgen receptor status may influence the effect of selenium on gene expression profile in prostate cancer; whether estrogen receptor may influence the effect of selenium on gene expression in breast cancer requires further studies. Knowledge from gene array data in combination with proteomics approaches, using homogenous population of cell types with the aid of laser capture microdissection, may provide an individualized dimension of information on cancer risk and potential targets for its prevention. The molecular (genetic) biomarkers presented in this review will provide the foundation for future studies of the chemopreventive properties of structurally varied selenium compounds.
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PMID:Molecular chemoprevention by selenium: a genomic approach. 1609 79

Here, we assessed and compared the anticancer efficacy and associated mechanisms of silymarin and silibinin in human prostate cancer (PCA) PC3 cells; silymarin is comprised of silibinin and its other stereoisomers, including isosilybin A, isosilybin B, silydianin, silychristin and isosilychristin. Silymarin and silibinin (50-100 microg/ml) inhibited cell proliferation, induced cell death, and caused G1 and G2-M cell cycle arrest in a dose/time-dependent manner. Molecular studies showed that G1 arrest was associated with a decrease in cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase (CDK)4, CDK6 and CDK2 protein levels, and CDK2 and CDK4 kinase activity, together with an increase in CDK inhibitors (CDKIs) Kip1/p27 and Cip1/p21. Further, both agents caused cytoplasmic sequestration of cyclin D1 and CDK2, contributing to G1 arrest. The G2-M arrest by silibinin and silymarin was associated with decreased levels of cyclin B1, cyclin A, pCdc2 (Tyr15), Cdc2, and an inhibition of Cdc2 kinase activity. Both agents also decreased the levels of Cdc25B and cell division cycle 25C (Cdc25C) phosphatases with an increased phosphorylation of Cdc25C at Ser216 and its translocation from nucleus to the cytoplasm, which was accompanied by an increased binding with 14-3-3beta. Both agents also increased checkpoint kinase (Chk)2 phosphorylation at Thr68 and Ser19 sites, which is known to phosphorylate Cdc25C at Ser216 site. Chk2-specific small interfering RNA largely attenuated the silymarin and silibinin-induced G2-M arrest. An increase in the phosphorylation of histone 2AX and ataxia telangiectasia mutated was also observed. These findings indicate that silymarin and silibinin modulate G1 phase cyclins-CDKs-CDKIs for G1 arrest, and the Chk2-Cdc25C-Cdc2/cyclin B1 pathway for G2-M arrest, together with an altered subcellular localization of critical cell cycle regulators. Overall, we observed comparable effects for both silymarin and silibinin at equal concentrations by weight, suggesting that silibinin could be a major cell cycle-inhibitory component in silymarin. However, other silibinin stereoisomers present in silymarin also contribute to its efficacy, and could be of interest for future investigation.
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PMID:Silymarin and silibinin cause G1 and G2-M cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells: a comparison of flavanone silibinin with flavanolignan mixture silymarin. 1620 33

2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with promise for cancer chemotherapy, including advanced prostate cancer. We have focused on events related to cell cycle arrest (G1 and G2/M) and induction of apoptosis in human prostate cancer cells. Treatment with 2-ME increased cyclin B1 protein and its associated kinase activity followed by later inhibition of cyclin A-dependent kinase activity and induction of apoptosis. Similar results were obtained with paclitaxel (taxol), a clinically relevant agent used to treat advanced prostate cancer. Cyclin-dependent kinase inhibitors prevented 2-ME and paclitaxel-mediated increase in cyclin B1-dependent kinase activity and blocked induction of apoptosis. Reduction of X-linked inhibitor of apoptosis (XIAP) protein by 2-ME and paclitaxel correlated with increased apoptosis. Lower doses of 2-ME and paclitaxel resulted in G1 (but not G2/M) cell cycle arrest in the p53 wild type LNCaP cell line, but with minimal induction of apoptosis. We suggest that 2-ME and paclitaxel-mediated induction of apoptosis in prostate cancer cells requires activation of cyclin B1-dependent kinase that arrests cells in G2/M and subsequently leads to the induction of apoptotic cell death.
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PMID:2-Methoxyestradiol and paclitaxel have similar effects on the cell cycle and induction of apoptosis in prostate cancer cells. 1635 31

High consumption of soy isoflavones in Asian diets has been correlated with a lower incidence of clinically important cases of prostate cancer. The chemopreventive properties of these diets may result from an interaction of several types of isoflavones, including genistein and daidzein. The present study investigated the effects of a soy isoflavone concentrate (ISF) on growth and gene expression profiles of PC-3 human prostate cancer cells. Trypan blue exclusion and [3H]-thymidine incorporation assays showed that ISF decreased cell viability and caused a dose-dependent inhibition of DNA synthesis, respectively, with 50% inhibition (IC50) of DNA synthesis at 52 mg/L (P = 0.05). The glucoside conjugates of genistein and daidzein in ISF were converted to bioactive free aglycones in cell culture in association with the inhibition of DNA synthesis. Flow cytometry and Western immunoblot analyses showed that ISF at 200 mg/L caused an accumulation of cells in the G2/M phase of the cell cycle (P < 0.05) and decreased cyclin A by 20% (P < 0.05), respectively. The effect of ISF on the gene expression profile of PC-3 cells was analyzed using Affymetrix oligonucleotide DNA microarrays that interrogate approximately 17,000 human genes. Of the 75 genes altered by ISF, 28 were upregulated and 47 were downregulated (P < 0.05). Further analysis showed that IL-8, matrix metalloproteinase 13, inhibin beta A, follistatin, and fibronectin mRNA levels were significantly reduced, whereas the expression of p21(CIP1), a major cell cycle inhibitory protein, was increased. The effects of ISF on the expression of IL-8 and p21(CIP1) mRNA and protein were validated at high and low ISF concentrations. Our data show that ISF inhibits the growth of PC-3 cells through modulation of cell cycle progression and the expression of genes involved in cell cycle regulation, metastasis, and angiogenesis.
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PMID:Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. 1636 62

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