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)

Oncoprotein 18 (Op18) is an intracellular phosphoprotein that has been shown to be overexpression in a number of human malignancies. In the present report we have studied the pattern of Op18 expression on normal, hyperplastic, and malignant prostatic tissue as well as in rat prostatic tumor lines. One of the objectives of the present work was to establish whether the level of Op18 expression can be used as a prognostic marker in human prostatic adenocarcinoma. To that end, sections from normal, hyperplastic, and malignant human prostatic tissue were examined by immunohistochemistry for expression of Op18. In the normal and hyperplastic prostate, Op18 expression was observed in basal glandular epithelial cells, whereas the columnar luminal epithelial cells were not stained by the anti Op18 antibodies. In highly differentiated prostatic cancers occasional epithelial cells were stained, while in poorly differentiated tumors most of the epithelial cells contained Op18 immunoreactivity. The staining pattern was similar in the primary prostatic tumor and in the regional lymph node metastases. Most importantly, a limited survey of prostatic cancer patient samples (n = 40) showed a significant correlation between the fraction of Op18 immunoreactive cells and survival. Studies of a rat prostatic tumor model, showed that only a few cells were stained in the highly differentiated Dunning R3327PAP tumor, while most cells were stained in the anaplastic AT1 rat prostatic tumor. Interestingly, castration of rats resulted in an increased Op18 immunoreactivity, within 14 days, in the highly differentiated rat R3327PAP prostatic tumor. In conclusion, the level of Op18 expression seems to be related to cellular differentiation, histological grade, and survival in prostatic cancers. These findings show that Op18 immunoreactivity may be useful as a prognostic marker in prostatic cancer. In addition it may help in the differentiation between highly differentiated prostatic tumors and non-malignant conditions.
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PMID:Differentiation-stage specific expression of oncoprotein 18 in human and rat prostatic adenocarcinoma. 763 82

We investigated the effect of protein kinase and phosphatase inhibitors on the growth of six human prostatic cancer cell lines: DU145, PC3, ND1, LNCaP, ALVA31 and JCA1. We studied okadaic acid and sodium orthovanadate as serine/threonine and tyrosine protein phosphatase inhibitors, respectively, and staurosporin and genistein as a serine/threonine and tyrosine protein kinase inhibitors, respectively. All inhibitors examined exhibited a dose-dependent growth inhibitory effect on prostatic cancer cell lines. Our data indicate that prostatic cancer cell lines express unique biochemical properties since the degree of growth inhibition varied greatly and was dependent on the specific cell line and inhibitor studied. In addition, we found that surface expression of endoglin (CD105) changed by treatment with all inhibitors in most of the cell lines. These data also indicate that endoglin appears to be involved both in protein phosphatase and kinase mediated phosphoprotein turnover.
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PMID:Differential sensitivity of human prostatic cancer cell lines to the effects of protein kinase and phosphatase inhibitors. 852 97

Androgen plays a critical role in regulating the growth and differentiation of normal prostate epithelia, as well as the initial growth of prostate cancer cells. Nevertheless, prostate carcinomas eventually become androgen-unresponsive, and the cancer is refractory to hormonal therapy. To gain insight into the mechanism involved in this hormone-refractory phenomenon, we have examined the potential role of the androgen receptor (AR) in that process. We have investigated the expression of AR and two prostate-specific androgen-responsive antigens, prostatic acid phosphatase (PAcP) and prostate-specific antigen (PSA), for the functional activity of AR in LNCaP and PC-3 human prostate carcinoma cells. Our results are as follows. (i) Clone 33 LNCaP cells express AR, PAcP, and PSA, and cell growth is stimulated by 5alpha-dihydrotestosterone (DHT). Stimulation of cell growth correlates with decreased cellular PAcP activity. (ii) In clone 81 LNCaP cells, the expression of PAcP decreases with a concurrent decrease in the degree of androgen stimulation of cell growth, whereas the expression of PSA mRNA level is up-regulated by DHT, as in clone 33 cells. Conversely, in PAcP cDNA-transfected clone 81 cells, an additional expression of cellular PAcP correlates with an increased stimulation by androgen, higher than the corresponding control cells. (iii) PC-3 cells express a low level of functional AR with no detectable PAcP or PSA, and the growth of PC-3 cells is not affected by DHT treatment. Nevertheless, in two PAcP cDNA-transfected PC-3 sublines, the expression of exogenous cellular PAcP correlates with androgen stimulation. This androgen stimulation of cell growth concurs with an increased tyrosine phosphorylation of a phosphoprotein of 185 kDa. In summary, the data indicate that the expression of AR alone is not sufficient for androgen stimulation of cell growth. Furthermore, in AR-expressing prostate cancer cells, the expression of cellular PAcP correlates with androgen stimulation of cell proliferation.
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PMID:Expression of human prostatic acid phosphatase correlates with androgen-stimulated cell proliferation in prostate cancer cell lines. 948 33

Estramustine (EM) is an anti-microtubule drug used in the treatment of hormone-refractory advanced prostate cancer. Since microtubules are the targets for EM cytotoxicity, we investigated the effects of EM on the microtubule-associated protein tau to determine what role it may play in drug resistance. We have compared tau expression in human prostate cancer cells (DU145) and an EM-resistant derived cell line (E4). Reverse transcriptase polymerase chain reaction has established that tau is expressed in both cell lines but increased 1.9-fold in E4 compared with DU145 cells. This result was confirmed at the protein level by Western blotting. Tau is a phosphoprotein, most of its reported phosphorylation sites being serine or threonine residues. We have shown, however, that tau is also phosphorylated at tyrosine residues in DU145 cells and that the phosphotyrosine level of tau is significantly increased in E4 cells. Moreover, DU145 cells exposed to short term micromolar drug concentrations enter a phase of microtubule depolymerization, display an increased level of tau phosphorylation and follow a pattern similar to that observed in EM-resistant E4 cells. EM is therefore able to induce a very rapid change in the posttranslational state of tau. Our results show that the acquisition of EM resistance in E4 cells, which is accompanied by changes at the tubulin level, is also associated with important changes in tau expression and phosphorylation.
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PMID:Estramustine resistance correlates with tau over-expression in human prostatic carcinoma cells. 967 68

Human prostatic acid phosphatase (PAcP) is a prostate epithelium-specific differentiation antigen. In prostate carcinomas, the cellular PAcP is decreased. We investigated its functional role in these cells. Several lines of evidence support the hypothesis that cellular PAcP functions as a neutral protein-tyrosine phosphatase and is involved in regulating prostate cell growth. In this study, we identify its in vivo substrate. Our results demonstrated that, in different human prostate cancer cell lines, the phosphotyrosine (Tyr(P)) level of a 185-kDa phosphoprotein (pp185) inversely correlates with the cellular activity of PAcP. On SDS-PAGE, this pp185 co-migrates with the c-ErbB-2 oncoprotein. Immunodepletion experiments revealed that c-ErbB-2 protein is the major pp185 in cells. Results from subclones of LNCaP cells indicated the lower the cellular PAcP activity, the higher the Tyr(P) levels of c-ErbB-2. This inverse correlation was further observed in PAcP cDNA-transfected cells. In clone 33 LNCaP cells, L-(+)-tartrate suppresses the cellular PAcP activity and causes an elevated Tyr(P) level of c-ErbB-2 protein. Epidermal growth factor stimulates the proliferation of LNCaP cells, which concurs with a decreased cellular PAcP activity as well as an increased Tyr(P) level of c-ErbB-2. Biochemically, PAcP dephosphorylates c-ErbB-2 at pH 7.0. The results thus suggest that cellular PAcP down-regulates prostate cell growth by dephosphorylating Tyr(P) on c-ErbB-2 oncoprotein in those cells.
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PMID:Tyrosine phosphorylation of c-ErbB-2 is regulated by the cellular form of prostatic acid phosphatase in human prostate cancer cells. 970 54

DOC-2/DAB2, a novel phosphoprotein with signal-transducing capability, inhibits human prostatic cancer cells (Tseng, C.-P., Ely, B. D., Li, Y., Pong, R.-C., and Hsieh, J.-T. (1998) Endocrinology 139, 3542-3553). However, its mechanism of action is not understood completely. This study delineates the functional significance of DOC-2/DAB2 protein phosphorylation and demonstrates that in vivo activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) induces DOC-2/DAB2 phosphorylation, including a serine residue at position 24. Mutation of Ser(24) to Ala reduced DOC-2/DAB2 phosphorylation by PKC. Using a synthetic Ser(24) peptide (APS(24)KKEKKKGSEKTD) or recombinant DOC-2/DAB2 as substrates, PKCbetaII, PKCgamma, and PKCdelta (but not casein kinase II) directly phosphorylated Ser(24) in vitro. This indicates that DOC-2/DAB2 is a PKC-specific substrate. Since expression of wild-type DOC-2/DAB2, but not the S24A mutant, inhibited TPA-induced AP-1 activity in prostatic epithelial cells, phosphorylation of Ser(24) appears to play a critical role in modulating TPA-induced AP-1 activity. Taken together, these data suggest that PKC-regulated phosphorylation of DOC-2/DAB2 protein may help its growth inhibitory function.
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PMID:The role of DOC-2/DAB2 protein phosphorylation in the inhibition of AP-1 activity. An underlying mechanism of its tumor-suppressive function in prostate cancer. 1054 28

The formation of mitotic centrosomes is a complex process in which a number of cellular proteins translocate to mitotic poles and play a critical role in the organization of the mitotic apparatus. The 238-kDa nuclear mitotic apparatus protein NuMA is one of the important proteins that plays a significant role in this process. NuMA resides in the nucleus during interphase and becomes transiently associated with mitotic centrosomes after multiple steps of phosphorylations. The role of NuMA in the interphase nucleus is not well known but it is clear that NuMA responds to external signals (such as hormones) that induce cell division, or heat shock that induces apoptosis. In order to determine the function of NuMA it is important to study its localization. Here we report on nuclear organization of NuMA during the cell cycle in estrogen responsive MCF-7 breast cancer cells and in androgen responsive LNCaP prostate cancer cells using immunoelectron microscopy, and on correlation to MPM-2 monoclonal phosphoprotein antibody. These results show that NuMA is present in speckled and punctate form associated with distinct material corresponding to a speckled or punctate immunofluorescence appearance in the nucleus while MPM-2 is uniformly dispersed in the nucleus. At prophase NuMA disperses in the cytoplasm and associates with microtubules while MPM-2 is uniformly distributed in the cytoplasm. During metaphase or anaphase anti-NuMA labeling is associated with spindle fibers. During telophase NuMA relocates to electron-dense areas around chromatin and finally to the reconstituted nuclei. These results demonstrate NuMA organization in MCF-7 and LNCaP cells in the log phase of cell culture growth.
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PMID:Immunolocalization of NuMA and phosphorylated proteins during the cell cycle in human breast and prostate cancer cells as analyzed by immunofluorescence and postembedding immunoelectron microscopy. 1144 86

Cyclooxygenase (COX) inhibitors have suppressive effects on several types of cancer cells including prostate cancer. In this study, we considered the potential COX-inhibitory activity of a unique anti-inflammatory herbal preparation (Zyflamend; New Chapter, Inc., Brattleboro, VT) and analyzed its effects on the human prostate cancer cell line LNCaP. COX inhibitory activity of Zyflamend was determined by a spectrophotometric-based assay using purified ovine COX-1 and COX-2 enzymes. Effects of Zyflamend on LNCaP cell growth and apoptosis in vitro were assessed by cell counting, Western blot detection of poly ADP-ribose polymerase (PARP) cleavage, and measurement of caspase-3 activity in treated and control cell extracts. Western blotting techniques were conducted to determine the effects of this herbal preparation on the expression of the cell signaling proteins, p21, androgen receptor (AR), phospho-protein kinase C (pPKC)(alpha/beta), and phospho (p)Stat3. The phospohorylation status of several signal transduction phosphoproteins was profiled using a high-throughput phosphoprotein screening assay in treated cells and compared to controls. Zyflamend dramatically decreased COX-1 and COX-2 enzymatic activity. Elevated p21 expression coincided with attenuated cell growth following treatment of LNCaP cells with Zyflamend. PARP cleavage fragments were evident, and caspase-3 activity was upregulated over the control indicating the ability of Zyflamend to induce apoptosis of these cells. Androgen receptor expression levels declined by 40%, and decreases were observed in the active forms of Stat3 and PKC(alpha/beta) in Zyflamend-treated LNCaP cells. Zyflamend inhibited both COX-1 and COX-2 enzymatic activities, suppressed cell growth, and induced apoptosis in LNCaP cells. However, our data suggests that the effects are likely due to COX-independent mechanisms potentially involving enhanced expression of p21 and reduced expression of AR, pStat3, and pPKC(alpha/beta).
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PMID:Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. 1620 51

Osteopontin is a secreted glycosylated phosphoprotein known to be involved in numerous physiologic functions and associated with the late stages of various cancers. We used preneoplastic and neoplastic mouse models of prostate cancer to determine the onset of elevated expression of osteopontin in the development of this disease. Osteopontin alterations occurred early in the disease with dysregulated expression observed in lesions of low-grade prostatic intraepithelial neoplasia (PIN). Over time, osteopontin expressing dysplastic cells seemed to increase in number in high-grade PIN and increased further in adenocarcinoma, and in metastasis, almost all of the cancer cells immunohistochemically stained positive for osteopontin overexpression. We examined the biological properties of human prostate cancer cell lines LNCaP and PC-3, in which osteopontin overexpression was achieved via lentiviral gene transduction. Evidence was obtained that osteopontin could contribute to a proliferative advantage in both cell types, although more significantly in LNCaP than PC-3. Osteopontin also influenced their in vitro invasive ability, and again, most strikingly in the weakly oncogenic LNCaP. Furthermore, excess osteopontin induced the LNCaP cells to acquire a strong intravasation potential in vivo in the chicken embryo chorioallantoic membrane assay for blood vessel penetration. These results establish a correlation between an increased gradient of osteopontin expression throughout the stages of murine prostate cancer, beginning from the preneoplastic lesions to distant metastases that suggests a proliferative and invasive advantages to those prostate tumor cells overexpressing osteopontin. Together, these findings support a strategy designed to target osteopontin in the context of prostate cancer therapy.
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PMID:Increased expression of osteopontin contributes to the progression of prostate cancer. 1642 21

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.
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PMID:Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells. 1846 90


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