Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although a large proportion of primary human breast cancers express the androgen receptor, and treatment with androgens exerts beneficial effects in women with breast cancer, the role and especially the mechanism of action of androgens in breast cancer development and growth are not well understood. The potential effect of androgens on bcl-2 protooncogene expression was investigated in a human breast cancer cell line whose proliferation is known to be inhibited by androgens. The estrogen-responsive ZR-75-1 cells were grown in the presence or absence of 5alpha-dihydrotestosterone (DHT), alone or in combination with 17beta-estradiol. DHT caused a marked down-regulation of Bcl-2 protein and messenger RNA levels in both the presence and absence of 17beta-estradiol. The inhibitory effect of DHT was completely prevented by coincubation with the pure antiandrogen hydroxyflutamide. The present data indicate that androgens can down-regulate bcl-2 protooncogene levels via an androgen receptor-mediated mechanism, thus providing a novel mechanism for their known inhibitory effect on breast cancer cell growth.
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PMID:Androgens down-regulate bcl-2 protooncogene expression in ZR-75-1 human breast cancer cells. 988 53

It was previously shown in the PC-295 xenograft that the number of chromogranin A (CgA)-positive neuroendocrine (NE) cells increased after androgen withdrawal. NE cells did not proliferate and differentiated from G0-phase-arrested cells. Here we further characterized NE differentiation, androgen receptor status, and apoptosis-associated Bcl-2 expression in the PC-295 model after androgen withdrawal to assess the origin of NE cells. PC-295 tumor volumes decreased by 50% in 4 days. Intraperitoneal bromodeoxyuridine (BrdU) incorporation and MIB-1 labeling decreased to 0%, and the apoptosis was maximal at day 4. Androgen receptor expression and prostate-specific antigen (PSA) serum levels decreased rapidly within 2 days. The number of NE cells increased 6-fold at day 4 and 30-fold at day 7. Five and ten percent of the CgA-positive cells were BrdU positive after continuous BrdU labeling for 2 and 4 days, respectively. However, no MIB-1 expression was observed in CgA-positive cells. NE cells expressed the regulated secretory pathway marker secretogranin III but were negative for androgen receptor and Bcl-2. Bcl-2 expression did increase in the non-NE tumor cells. In conclusion, androgen withdrawal leads to a rapid PC-295 tumor regression and a proliferation-independent induction of NE differentiation. The strictly androgen-independent NE cells that were still present after 21 days differentiated mainly from G0-phase-arrested cells.
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PMID:Kinetics of neuroendocrine differentiation in an androgen-dependent human prostate xenograft model. 1002 12

Androgen ablation-induced prostate cancer regression is transient and ends with the regrowth of androgen-independent (AI) tumors. To mimic this evolution in culture, we chronically deprived an androgen-dependent (AD) prostate cancer cell line (LNCaP) of androgen, generating an AI derivative which retained limited hormone proliferative responsiveness and a barely detectable prostate-specific antigen (PSA) mRNA level. While the cytokeratin 8 (CK8) level was low, the androgen receptor (AR) protein in AI cells was on average tenfold greater than in AD cells. When challenged for susceptibility to undergo apoptosis, the AI cells were more resistant than AD cells to all-trans retinoic acid (tRA) and two chemotherapeutic agents, Taxol and Adriamycin, requiring higher doses and longer periods of treatment to achieve similar effects. Compared to AD cells, the partially apoptosis-resistant AI cells expressed four times more Bcl-2 protein and undetectable levels of p21/WAF1. Induction of apoptosis by tRA in both cell types did not affect their expression but was preceded by the activation of Rb and a pronounced reduction of AR protein level. The kinetics of the Rb activation and AR downmodulation in both cell types matched their tRA sensitivity, suggesting that these events may be required for tRA-induced apoptosis. The results show that the apoptotic pathway in AI cells, although more difficult to induce, is not irrevocably lost and that targeted reduction of the AR protein level with retinoids in combination with androgen ablation therapy may prolong remissions in advanced prostate cancer patients.
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PMID:Activation of Rb and decline in androgen receptor protein precede retinoic acid-induced apoptosis in androgen-dependent LNCaP cells and their androgen-independent derivative. 1022 52

Proliferation in the setting of longstanding chronic inflammation appears to predispose to carcinoma in the liver, large bowel, urinary bladder, and gastric mucosa. Focal prostatic atrophy, which is associated with chronic inflammation, is highly proliferative (Ruska et al, Am J Surg Pathol 1998, 22:1073-1077); thus the focus of this study was to more fully characterize the phenotype of the atrophic cells to assess the feasibility of the proposal that they may be targets of neoplastic transformation. The pi-class glutathione S-transferase (GSTP1), a carcinogen-detoxifying enzyme, is not expressed in >90% of prostate carcinomas (CaPs). GSTP1 promoter hypermethylation, which appears to permanently silence transcription, is the most frequently detected genomic alteration in CaP (Lee et al, Proc Natl Acad Sci USA 1994, 91:11733-11737; >90% of cases). In high-grade prostatic intraepithelial neoplasia (PIN), this alteration is present in at least 70% of cases (Brooks et al, Cancer Epidemiol Biomarkers Prev, 1998, 7:531-536). Although normal-appearing prostate secretory cells rarely express GSTP1, they remain capable of expression, inasmuch as GSTP1 promoter hypermethylation is not detected in normal prostate. Fifty-five lesions from paraffin-embedded prostatectomy specimens (n = 42) were stained for GSTP1, using immunohistochemistry. Adjacent sections were stained for p27(Kip1), Ki-67, androgen receptor (AR), prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSAP), Bcl-2, and basal cell-specific cytokeratins (34betaE12). With normal prostate epithelium as the internal standard, staining was scored for each marker in the atrophic epithelium. The lesions showed two cell types, basal cells staining positive for 34betaE12, and atrophic secretory-type cells staining weakly negative for 34betaE12. All lesions showed elevated levels of Bcl-2 in many of the secretory-type cells. All lesions had an elevated staining index for the proliferation marker Ki-67 in the secretory layer and decreased expression of p27(Kip1), a finding reminiscent of high-grade PIN (De Marzo et al, Am J Pathol 1998, 153:911-919). Consistent with partial secretory cell differentiation, the luminal cells showed weak to moderate staining for androgen receptor and the secretory proteins PSA and PSAP. All atrophic lesions showed elevated GSTP1 expression in many of the luminal secretory-type cells. Because all lesions are hyperproliferative, are associated with inflammation, and have the distinct morphological appearance recognized as prostatic atrophy, we suggest the term "proliferative inflammatory atrophy" (PIA). Elevated levels of GSTP1 may reflect its inducible nature in secretory cells, possibly in response to increased electrophile or oxidant stress. Elevated Bcl-2 expression may be responsible for the very low apoptotic rate in PIA and is consistent with the conclusion that PIA is a regenerative lesion. We discuss our proposal to integrate the atrophy and high-grade PIN hypotheses of prostate carcinogenesis by suggesting that atrophy may give rise to carcinoma either directly, as previously postulated, or indirectly by first developing into high-grade PIN.
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PMID:Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. 2017 14

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

Apocrine ductal carcinoma in situ (ADCIS) has been called a special type of ductal carcinoma in situ (DCIS) because the histologic grading is considered difficult using the classification schemes that have been proposed for common DCIS. However, ADCIS encompasses a spectrum of lesions with different morphologic aspects ranging from minimally atypical to overtly malignant. To define a classification scheme for ADCIS, 35 cases (22 pure and 13 associated with invasive carcinoma) were selected on the basis of conventional morphology on hematoxylin and eosin (H&E)-stained sections. Each case was assigned to 1 of 3 histologic grades (low, intermediate, and high) based on nuclear morphology and the presence of necrosis. In addition, the expression of hormone receptors p53, bcl-2, c-erbB-2, and Ki-67 was evaluated by immunohistochemistry, and the DNA ploidy was determined by image cytometry. Fifteen cases were classified as high histologic grade, 10 as low histologic grade, and the other 10 as intermediate grade. All but 4 cases, irrespective of grade, had the same hormonal immunophenotype: androgen receptor positivity (97.1%) and estrogen receptor and progesterone receptor negativity (94.3% and 97.1% respectively). Twenty-one cases (61.8%) showed p53 expression, and 47.1% of the cases were positive for c-erbB-2. The median positivity for Ki-67 was 5.2%. ADCIS has a unique morphologic and hormonal profile, distinct from common DCIS, deserving a specific classification. The proposed classification scheme allows for categorization of ADCIS according to the most important morphologic features already seen in common DCIS, ie, nuclear grade and necrosis. The expression of biologic markers other than hormonal receptors and bcl2 in ADCIS seems in general to be similar to that in common DCIS. Ki-67 and c-erbB-2 are expressed more frequently in intermediate and high histologic grade ADCIS.
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PMID:Apocrine ductal carcinoma in situ of the breast: histologic classification and expression of biologic markers. 1138 66

Moleculo-genetic pathways of development and progression of prostate cancer have been studied. In the norm, paracrine regulation of the glandular secretory epithelium are predominant due to the influence of hormonal and protein factors of the stroma. The altered prostatic epithelium becomes independent from the stroma and androgens and, consequently, prone to metastasizing, following activation of protooncogenes (growth factor genes), inactivation of gene-suppressors, hyperexpression of certain growth factors and apoptosis inhibitor Bcl-2, and inactivation of androgen receptor. In inoperable prostate cancer, palliative treatment should include antiandrogen therapy, inhibition of growth factors and activation of apoptosis. Prevention and medication for prostate cancer targeting apoptosis, growth factors and androgens should be based on recent achievements in experimental genotherapy and selective use of proliferation inhibitors and apoptosis activators which are to be fed to the gland via viral and non-viral vectors. Molecular-biological markers of risk for cancer, its early detection, prognosis of clinical course and effectiveness of treatment are discussed. A modality for laboratory diagnosis and complex treatment of prostate cancer offering maximum survival so far has been suggested.
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PMID:[Hormonal and molecular biological factors in pathogenesis of prostate cancer]. 1138 53

The study of the prognostic criteria of hormone-resistant prostatic cancer (PC) by specifying expression of androgen receptor protein as well as Bcl-2 and p53 proteins, apoptosis regulators, has demonstrated that tumor cells of hormone-sensitive and hormone-resistant PC forms have different variants of immunophenotype. Hormone-resistance is typical for tumors from urothelial, basal and neuroendocrine PC cells, glandular epithelium cells which lost androgen receptors (AR) and tumors consisting of cells which retain AR but simultaneously express Bcl-2 and/or p53 genes. The discovery of androgen-resistant cancer from glandular epithelium which has immunophenotype characteristics of a hormone-dependent tumor indicates the existence of other mechanisms of protection against apoptosis. The development of hormone-resistant cancer 2.5-3 years after hormonal therapy is associated with changes in immunophenotype of tumor cells. They become Bcl-2- and/or p53-positive while part of them lose AR. Thus, immunophenotype of tumor cells may serve a prognostic marker of hormonal resistance of the tumor and dictate the treatment policy.
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PMID:[Hormone-resistant epithelial cancer of the prostate]. 1156 31

Members of the bcl-2 gene family and endogenous inhibitors of cyclin-dependent kinases participate in the regulation of apoptosis and cell cycle in a diverse range of cell types and are implicated in the development of hormone refractory prostate cancer and resistance to anti-cancer therapy. The expression of several of these genes can be regulated by steroid hormones and related agents via their nuclear receptors. However, insufficient information considering the protein expression after the treatment by hormone antagonists is available. The aim of this study was to evaluate the expression of anti- and pro-apoptotic proteins, (Bcl-2, Bax), and to correlate this with the appearance of some nuclear receptors and cell cycle related proteins in androgen sensitive and androgen insensitive prostate cancer cell lines, LNCaP and DU-145, after the treatment by androgen antagonist bicalutamide. Our results revealed that androgen receptor (AR) expression in LNCaP cells decreased, however in DU-145 cells AR slightly increased following anti-androgen treatment. The same agent stimulated expression of p21Waf1/Cip5 and p27Kip1 in LNCaP, as well as in DU-145 cell lines. Bcl-2 level increased slightly in LNCaP cells and, in DU-145 cells was almost undetectable. Bax expression was not changed in LNCaP but significantly decreased in DU-145 cells. Similarly, retinoid X receptor beta (RXRbeta) level was significantly down regulated after 24 hours in DU-145 and also in LNCaP cells after 72 hours. These results confirm that androgen withdrawal therapy employing anti-androgens may elicit different signalling pathways in various types of prostate cancer that may be dependent on AR status and AR sensitivity.
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PMID:Androgen sensitivity related proteins in hormone-sensitive and hormone-insensitive prostate cancer cell lines treated by androgen antagonist bicalutamide. 1184 89

Multiple molecular, cellular, structural, and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively, or they may succumb to neurodegenerative cascades that result in disorders such as Alzheimer's and Parkinson's diseases. Multiple mechanisms are employed to maintain the integrity of nerve cell circuits and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g., protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), preservation of genomic integrity by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of Alzheimer's disease (amyloid precursor protein and presenilins), Parkinson's disease (alpha-synuclein and Parkin), and trinucleotide repeat disorders (huntingtin, androgen receptor, ataxin, and others) overwhelm endogenous neuroprotective mechanisms; other genes, such as those encoding apolipoprotein E(4), have more subtle effects on brain aging. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction and folate and antioxidant supplementation) and behavioral (intellectual and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response in which neurons increase production of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modern methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.
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PMID:Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. 1208 31


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