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)

Tumor suppressor gene p16 is a cyclin-dependent kinase inhibitor and an important negative cell cycle regulator. The inactivation of p16 appears to be a common event in prostate cancer. Replacement of p16 inhibits prostate tumor cell growth, but the mechanism is not known. Human prostate cancer cell lines PPC-1, which has an inactivated p16, and DU145, which has a nonfunctional retinoblastoma Rb protein (pRb), were used to determine the possible mechanism of p16 mediated growth inhibition. PPC-1 cells treated with 5-aza-2'-deoxycytidine (5-aza-dC), a demethylating agent, induced p16 expression, inhibited cell growth, and induced senescence. Similarly, PPC-1 cells transduced by an adenoviral vector containing the p16 gene (AdRSVp16) produced a p16 protein that suppressed cellular proliferation and induced senescence. Co-staining of AdRSVp16-transduced PPC-1 cells by p16 immunohistochemistry and by beta-galactosidase substrate X-gal showed that the morphologically enlarged cells expressed both p16 and senescence-associated beta-galactosidase. In contrast, AdRSVp16 did not induce senescence in DU145 cells, but did inhibit its growth. However, when wild-type pRb was introduced in DU145 cells, AdRSVp16 was able to induce senescence. Thus, the mechanism by which p16 suppressed prostate cancer was dependent on the pRb functional status of cells whereby p16 caused pRb+ cells to undergo inhibition by senescence, whereas pRb- cells were also inhibited, but not by senescence.
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PMID:p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways. 1071 71

We established two human prostate cancer cell lines, MDA PCa 2a and MDA PCa 2b, the TabBO model system, that reflect common features of human androgen-independent prostate cancer that are not present in other model systems: bone origin, prostate-specific antigen production, androgen receptor expression, and androgen sensitivity. We therefore hypothesized that molecular pathways in our model system reflect common alterations responsible for the progression of a subset of human prostate cancer. Progression to androgen independence has been hypothesized to be largely associated with impairment of the regulation of cell growth or apoptosis of prostate cancer cells. Therefore, in this study, we examined molecular markers known or suspected to be important in prostate cancer progression and key regulators of cell growth and apoptosis: p53, p21WAF1/CIP1, Bcl-2, Bax, retinoblastoma (Rb), and p16INK4A/MITS1. We analyzed the expression of these markers in the cell lines, their tumor of origin, and tumors derived from the cell lines by s.c. inoculation into nude mice. DNA sequencing of the entire open reading frames of the p53 and p21 genes revealed no mutations. Additionally, accumulation of the p53 protein was not found by Western blot analysis, nor was overexpression of the Bcl-2 oncoprotein detected. Bax expression was detected in MDA PCa 2a cells, whereas it was absent in MDA PCa 2b. Rb and p16 protein expression was normal as measured by both Western blot and immunochemical analyses. Immunohistochemical studies of p53, p21, Bcl-2, and Rb in both samples from the original human cancer from which the lines were derived and mouse xenografts derived from the lines revealed similar levels of protein. These results are consistent with reports indicating that 40-50% of bone metastases of prostate cancer have wild-type p53, 50-70% do not overexpress the Bcl-2 protein, and mutations in the p21 gene are rare. Therefore, we conclude that MDA PCa 2a and MDA PCa 2b reflect molecular pathways in a common subset of human androgen-independent prostate cancer and that important molecular players in apoptosis (namely, p53 and Bcl-2) seem to be intact in this subset of androgen-independent prostate cancer. Understanding the signal-transduction pathways operating in these cell lines may help to identify therapeutic targets for prostate cancer.
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PMID:TabBO: a model reflecting common molecular features of androgen-independent prostate cancer. 1074 51

Like many other carcinomas, prostate cancer develops resistance to inhibition by transforming growth factor (TGF)-&be;1 during oncogenesis. One proposed mechanism of TGF-&be;1 action posits action of the retinoblastoma protein (pRb) to suppress c-myc transcription to inhibit cellular proliferation. A metastatic human prostate cancer cell line, DU145, has both nonfunctional pRb and markedly reduced sensitivity to TGF-&be;1 growth inhibition. The defective rb gene in DU145 cells was replaced by a normal rb allele by microcell fusion of chromosome 13. Two subclones, DU145-Cl-I and DU145-Cl-II, were studied in vitro to determine whether the pRb restoration increased sensitivity to the inhibitory effects of TGF-&be;1. By reverse transcriptase-polymerase chain reaction, increased sensitivity to the inhibitory effects of TGF-&BE;1. By reverse transcriptase-polymerase chain reaction, parental DU145 cells had TGF-b receptors of Type I and Type II. Introduction of chromosome 13 reduced the growth rate and prolonged the G1 phase compared with the parental DU145 cell line. Moreover, responsiveness to TGF-&be;1 growth inhibition was restored in a dose-dependent manner. Transcription of c-myc was not altered by TGF-&be;1 growth inhibition. Thus, DU145 cells presumably required the presence of wildtype rb to become growth inhibited that is independent of c-myc transcription. As the entire chromosome 13 was introduced, unknown tumor suppressor genes, not only rb, may be responsible for the restoration of TGF-&be;1 growth inhibition.
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PMID:Introduction of Human Chromosome 13 into Retinoblastoma-Negative Metastatic Human Prostate Cancer Cells Increases Their Sensitivity to Growth Inhibition by Transforming Growth Factor-&be;1. 1085 18

Surgery, radiation, or hormone deprivation alone does not adequately affect local control of clinical or pathologic stage T3 prostate cancer. Lack of local cancer control ultimately leads to a higher incidence of morbidity, distant metastasis, and decreased survival, with patients having disease-specific mortality exceeding 75%. Other novel therapies against this devastating and common disease are needed for the achievement of long-term local cancer control. For this purpose, therapeutic interventions should target prostate-cancer cells at the molecular and cellular level in ways not possible by current modalities of cancer treatment. Any strategy that can modify the biologic behavior of these cells may potentially have the most significant clinical impact. As prostate cancer represents an accumulation of genetic mutations that causes a prostate cell to lose the ability to control its growth, one new approach against prostate cancer may be gene therapy. Identification of key missing or mutated tumor-suppressor genes that, when replaced, may inhibit or destroy prostate-cancer cells may have the best chance of clinical success. One such gene appears to be tumor-suppressor gene p16 (also known as MTS1, INK4A, and CDKN2). Tumor-suppressor gene p16 is an important negative cell-cycle regulator whose functional loss may significantly contribute to malignant transformation and progression. Alterations in the p16 gene and its protein expression often occur in prostate cancer. An adenoviral vector containing wild-type p16 (Adp16) had a high transduction efficiency in prostate-cancer cells both in vitro and in vivo. Moreover, prostate tumors injected with Adp16 expressed p16 and the adenoviral vector expressed the transgene for up to 14 days. Wild-type p16 inhibited prostate-cancer proliferation in vitro and markedly suppressed tumors in vivo. Pathologic evaluation of the Adp16-treated tumors showed dose-dependent necrosis and fibrosis. Although the mechanism of p16 inhibition in cancer remains to be elucidated, senescence and apoptosis may both be important; however, the data suggest that p16-induced growth inhibition can function independently of the retinoblastoma gene product.
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PMID:Adenovirus p16 gene therapy for prostate cancer. 1085 45

Farnesyltransferase inhibitor (FTI) induces apoptosis of transformed cells. This involves changes in mitochondria, including decrease of mitochondrial membrane potential and the release of cytochrome c. The released cytochrome c then induces events leading to the activation of caspase-3. In this study, we report that purine derivative cyclin-dependent kinase (Cdk) inhibitors, roscovitine and olomoucine, dramatically enhance this FTI-induced apoptosis of human cancer cell lines. We noticed the synergy between Cdk inhibitors and FTI through our screen to identify compounds that enhance FTI-induced apoptosis of promyelocytic leukemic cell line HL-60. The Cdk inhibitors by themselves do not induce apoptosis at the concentrations used. Roscovitine synergizes with FTI to release cytochrome c from mitochondria. In addition, we detected synergistic effects of FTI and roscovitine to inhibit hyperphosphorylation of retinoblastoma protein. Enhancement of FTI-induced apoptosis by roscovitine is not unique to HL-60 cells, since similar synergy was observed with a leukemic cell line CEM and a prostate cancer cell line LNCaP. In LNCaP cells, in addition to roscovitine and olomoucine, phophatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, was effective in enhancing FTI-induced apoptosis. However, the effects of roscovitine appear to be distinct from those of LY294002, since roscovitine did not affect Akt activity while LY294002 significantly decreased the activity of Akt. Our finding of the synergy between FTI and Cdk inhibitor is significant for understanding the mechanism of action of FTI as well as for clinical use of FTI.
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PMID:Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines. 1087 58

Prostate cells are dependent on androgen for proliferation, but during tumor progression prostate cancer cells achieve independence from the androgen requirement. We report that androgen withdrawal fails to inhibit cell cycle progression or influence the expression of cyclin-dependent kinase (CDK)/cyclins in androgen-independent prostate cancer cells, indicating that these cells signal for cell cycle progression in the absence of androgen. However, phosphorylation of the retinoblastoma tumor suppressor protein (RB) is still required for G1-S progression in androgen-independent cells, since the expression of constitutively active RB (PSM-RB) or p16ink4a caused cell cycle arrest and mimicked the effects of androgen withdrawal on downstream targets in androgen-dependent LNCaP cells. Since Ras is known to mediate mitogenic signaling to RB, we hypothesized that active V12Ras would induce androgen-independent cell cycle progression in LNCaP cells. Although V12Ras was able to stimulate ERK phosphorylation and induce cyclin D1 expression in the absence of androgen, it was not sufficient to promote androgen-independent cell cycle progression. Similarly, ectopic expression of CDK4/cyclin D1, which stimulated RB phosphorylation in the presence of androgen, was incapable of inactivating RB or driving cell cycle progression in the absence of androgen. We show that androgen regulates both CDK4/cyclin D1 and CDK2 complexes to inactivate RB and initiate cell cycle progression. Together, these data show that androgen independence is achieved via deregulation of the androgen to RB signal, and that this signal can only be partially initiated by the Ras pathway in androgen-dependent cells.
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PMID:Differential requirements for ras and the retinoblastoma tumor suppressor protein in the androgen dependence of prostatic adenocarcinoma cells. 1093 90

The underlying causes for different apoptotic responses in neoplastic cells are still not fully understood. We demonstrate here that a human breast cancer cell line, MDA-MB-468, which lacks the retinoblastoma protein (RB), is particularly sensitive to low doses of ultraviolet (UV) radiation. These cells are 15-20-fold more sensitive to UV radiation than RB-positive cell lines, as measured by both apoptosis and clonogenic assays. In addition, a prostate cancer cell line that lacks functional RB, DU-145, was found to have a similar apoptotic response to low doses of UV radiation. Based on these data, we hypothesized that the lack of RB is responsible for the extreme sensitivity of these cells to UV-radiation-induced apoptosis. To further examine the role of RB in apoptosis, cells of RB-positive human breast cancer and normal cell lines were infected with the human papilloma virus type 16 (HPV-16) E7 and assessed for UV-radiation sensitivity. The HPV-16 E7 protein is known to decrease levels of free RB in cells. Infection of RB-positive human breast cancer or normal cells with E7 resulted in a 4-5-fold increase in sensitivity to UV radiation compared to controls. The above data suggest a role for the RB protein in protecting cells from undergoing apoptosis in response to UV radiation.
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PMID:Lack of RB protein correlates with increased sensitivity to UV-radiation-induced apoptosis in human breast cancer cells. 1102 55

Treatment with millimolar concentrations of phenylacetate (PA), results in cytostasis, growth inhibition and differentiation in several human cancer cell lines, including prostate cancer. However, the molecular basis of PA-induced biological effects has not been elucidated in detail. In this study we focused on its influence on cell cycle events and investigated alterations in cell cycle regulators in androgen-dependent and independent human prostate cancer cell lines. FACS analysis revealed that suppression of cell growth by PA was due to G1 arrest, with reduced phosphorylation of the retinoblastoma protein (pRb) and CDK2 activity. Expression of p27Kip1 was increased, while p21Cip1, p53, cyclinD1 and cyclin E were not affected by PA. Binding of p27Kip1 to CDK2 increased significantly following treatment with PA. Furthermore, antisense p27Kip1 oligonucleotide attenuated the inhibitory effect of PA. Our results suggested that p27Kip1 might be a critical target in PA-mediated cell growth arrest in prostate cancer cells playing a key role in CDK2 inactivation followed by hypophosphorylation of pRB and subsequent G1 cell cycle arrest.
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PMID:p27Kip1 is the key mediator of phenylacetate induced cell cycle arrest in human prostate cancer cells. 1106 25

The retinoblastoma (Rb) gene product is a prototypic tumor suppressor. Mice lacking the Rb gene are not viable and die in utero at approximately 13 days of gestation. In this study, we have rescued Rb-/- prostates by grafting pelvic organ rudiments from Rb-/- mouse embryos under the renal capsule of adult male nude mouse hosts. Grafts of embryonic pelvic organs developed into functional prostatic tissue. Some of the prostatic tissue generated was further used to construct chimeric prostatic tissue recombinants by combining wild-type rat urogenital mesenchyme (rUGM) with Rb-/- and Rb+/+ prostatic epithelium (PRE). The tissue recombinants were grown as subcapsular renal grafts and treated from the time of grafting with Silastic capsules containing 25 mg of testosterone plus 2.5 mg of estradiol. During 5-8 weeks of hormone treatment, rUGM+Rb+/+PRE tissue recombinants developed prostatic hyperplasia, whereas PRE in rUGM+Rb-/-PRE tissue recombinants developed hyperplasia, atypical hyperplasia, and carcinoma. During carcinogenesis in rUGM+Rb-/-PRE tissue recombinants, prostatic epithelial cells of the basal lineage disappeared, whereas the luminal cells underwent carcinogenesis. Epithelial E-cadherin almost totally disappeared. In all cases, epithelial PCNA labeling was elevated in tissue recombinants containing Rb-/- versus Rb+/+ epithelium. These epithelial changes were associated with almost total loss of smooth muscle cells in the stroma. In contrast, in untreated hosts rUGM+Rb+/+PRE tissue recombinants developed normally, and rUGM+Rb-/-PRE tissue recombinants developed mild epithelial hyperplasia. The results of this study demonstrate that Rb-/- prostatic tissue can be rescued from embryonic lethal mice and used to test its susceptibility to hormonal carcinogenesis. Deletion of the Rb gene predisposes prostatic epithelium to hyperplasia and increases proliferative activity Susceptibility to hormonal carcinogenesis in response to exogenous testosterone + estradiol is manifested in the progression from atypica hyperplasia to carcinoma. Thus, these findings demonstrate that the absence of the Rb tumor suppressor gene may predispose prostatic epithelial cells to carcinogenesis. Rescue of organs from Rb-/- embryos not only provides an opportunity to analyze the Rb gene pathway in the development and progression of prostate cancer but also provides an opportunity for specifically evaluating the role of the Rb pathway in development and carcinogenesis in other organs, such as the mammary gland and colon. Because rUGM greatly stimulates prostatic epithelial proliferation, the tissue recombinant model is a particularly useful tool for assessing the functional role of other genes in prostatic carcinogenesis through use of the appropriate transgenic or gene knockout mice.
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PMID:Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue. 1108 21

Androgens exert a peculiar biphasic dose-dependent influence on the proliferation of LNCaP cells, a widely used model to study androgen effects on prostate cancer cells. Low concentrations of androgen stimulate proliferation, but high concentrations inhibit proliferation and induce strong expression of differentiation markers. In order to gain more insight into the molecular mechanisms that underlie these changes we studied the influence of a wide concentration range of the synthetic androgen R1881 on several cell cycle- and differentiation-related parameters. Low concentrations (0.1 nM), known to promote LNCaP cell proliferation, induce an increase of Retinoblastoma protein phosphorylation, accompanied by an increase of E2F-1 protein levels and E2F activity and by increased expression of the E2F-target gene products E2F-1 and cyclin A. High concentrations of R1881 (10 nM) induce strong expression of the differentiation marker prostate-specific antigen. Retinoblastoma protein is largely hypophosphorylated, resulting in low E2F activity and low concentrations of E2F-1 and cyclin A mRNA. Finally, there is a strong increase of p27(KIP1) protein, but not of p27(KIP1) mRNA. These results indicate that the biphasic dose response of LNCaP proliferation to androgen is closely reflected in Rb phosphorylation, E2F activity and p27(KIP1) protein expression.
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PMID:E2F activity is biphasically regulated by androgens in LNCaP cells. 1132 73


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