Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clonally derived C-, D-, and T-family AXC/SSh rat prostate cancer cell lines contain transforming growth factor-beta (TGF beta) receptors. The content in C3, D1, T1, and T5 cells, respectively, was 8,560 +/- 1,450, 13,160 +/- 1,240, 2,425 +/- 490, and 10,540 +/- 1,025 sites/cell (mean +/- SEM). Respective Kd values were 160 +/- 48, 200 +/- 53, 24 +/- 3, and 115 +/- 15 pM (mean +/- SEM). T1 cell TGF beta receptor site content and Kd differed significantly from those of other prostate cancer cell lines (P less than 0.05). TGF beta is a bifunctional concentration-dependent modulator of T1 and T5 cell thymidine incorporation. At low concentrations, thymidine incorporation was inhibited, whereas as the medium TGF beta content was increased, T1 and T5 cell thymidine incorporation was stimulated. The concentrations of TGF beta causing half-maximum inhibition of T1 or T5 cell thymidine incorporation, respectively, were 0.11 and 0.24 pM, whereas the respective TGF beta concentrations causing half-maximum stimulation of thymidine incorporation were 14.4 and 134 pM. These findings establish that rat prostate cancer cell sensitivity to TGF beta inhibition of function is at least 2 orders of magnitude greater than that of most other mammalian cells. In contrast, the sensitivity of rat prostate cancer cells to TGF beta enhancement of function is comparable to that of other mammalian cells. TGF beta inhibited basic fibroblast growth factor (bFGF) stimulation of T1 and T5 cell thymidine incorporation. Because the concentration of bFGF required for half-maximum increase of T5 cell thymidine incorporation was independent of medium TGF beta content, the effect of TGF beta is distal to the T5 cell bFGF receptor. In contrast, the concentration of bFGF required for half-maximum increase in T1 cell thymidine incorporation increased 5-fold as the medium TGF beta content was increased; suggesting that the effect of TGF beta in T1 cells is proximal to the T1 cell bFGF receptor. Our studies establish that rat prostate cancer cells contain functional TGF beta receptors, imply the presence of functional bFGF receptors, and demonstrate that mitogen modulation of prostate cancer cell function is multifactorial. The finding that TGF beta is a bifunctional effector of prostate cancer cell DNA synthesis provides some insight into the potential complexity of mitogen modulation of prostate cancer cell proliferation. The mechanism by which these mitogens interact is unknown; however, our studies suggest that some interactive effects may be cell line specific.
 ...
PMID:Rat prostate cancer cells contain functional receptors for transforming growth factor-beta. 215 28

Recent advances in culture techniques have enabled routine establishment and propagation of epithelial cells derived from normal and malignant tissues of the human prostate. Comparative studies of the responses of normal and cancer-derived cell populations to various growth and differentiation factors in vitro were undertaken to examine the possibility that cancer cells might respond differentially. Clonal growth assays in serum-free medium demonstrated that optimal proliferation of normal as well as cancer cell strains was generally dependent on the presence of cholera toxin, epidermal growth factor, pituitary extract, hydrocortisone, insulin, and high levels of calcium in the culture medium, and on the use of collagen-coated dishes. Only one cancer strain responded aberrantly to epidermal growth factor and hydrocortisone. Putative differentiation factors (transforming growth factor-beta and vitamin A) inhibited the growth of all normal and cancer strains. The origin of a cancer-derived cell strain that responded similarly to normal strains was verified by positive labeling with a prostate cancer-specific antibody, validating the conclusion from these studies that normal and cancer prostatic epithelial cells are not distinguishable on the basis of responses to the tested factors.
 ...
PMID:In vitro studies of human prostatic epithelial cells: attempts to identify distinguishing features of malignant cells. 269 20

The RRR-alpha-tocopheryl succinate derivative of vitamin E, referred to as vitamin E succinate (VES), inhibits the proliferation of three metastatic human prostatic cancer cell lines, LNCaP, PC-3, and DU-145. LNCaP is a lymph node-derived androgen-sensitive prostate cell line; these cells are defective for response to transforming growth factor-beta (TGF-beta) but are normal for cell cycle-related tumor suppressor genes: p53 and retinoblastoma (Rb). PC-3 is a bone marrow-derived androgen-insensitive prostate cell line; these cells are defective for both p53 alleles but normal for both Rb alleles. DU-145 is a brain-derived androgen-insensitive prostate cell line; these cells are defective for both p53 and both Rb alleles. VES at 5, 10, and 20 micrograms/ml inhibited DNA synthesis in the three cell lines in a dose-dependent manner. Purified TGF-beta 1 at 1 ng/ml inhibited DNA synthesis of PC-3 cells within 24-72 hours and DU-145 cells at 72 hours but did not inhibit DNA synthesis of LNCaP cells. Previous studies in our laboratory showed that VES growth-inhibited tumor cells secrete biologically active antiproliferative factor TGF-beta s, suggesting that VES's mechanism of growth inhibition may involve the TGF-beta system of growth control.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:RRR-alpha-tocopheryl succinate inhibits the proliferation of human prostatic tumor cells with defective cell cycle/differentiation pathways. 858 52

LNCaP is an androgen-responsive prostatic cancer cell line that exhibits a bell-shaped growth response to increasing doses of dihydrotestosterone (DHT) in culture. Although the precise mechanism responsible for this growth response to androgen stimulation remains unclear, many studies have suggested that androgen modulates the level of various growth factors. In the present study, the role of transforming growth factor-beta (TGF-beta) in mediating the androgen-regulated growth arrest of LNCaP cells was investigated. The following concentrations of DHT were used: 0, 10(-12), 10(-10), and 10 (-7) M. These concentrations were selected because they represent the zero DHT control, the low-proliferative dose, the high-proliferative dose, and the growth arrest dose, respectively. Results of RT-PCR showed that LNCaP cells express TGF-beta1 but not -beta2 and -beta3 messenger RNA. Competitive quantitative RT-PCR demonstrated that the level of TGF-beta1 messenger RNA increased approximately 7-fold when cells were treated with 10(-7) M DHT. Results of Western blot analysis showed a dramatic increase in the level of latent TGF-beta1 protein in cell lysates with increasing concentrations of DHT. In addition, results of enzyme-linked immunoadsorbent assay for TGF-beta1 indicated that treatment of LNCaP cells with DHT led to a dose-dependent increase in both total and biologically active TGF-beta1 in the conditioned media. To determine the role of TGF-beta1 in regulating LNCaP proliferation, the action of TGF-beta1 was blocked by two different but complementary approaches. First, TGF-beta1 neutralizing antibody was added to the culture medium with varying concentrations of DHT. Second, mannose-6-phosphate, which has been demonstrated to inhibit the activation of latent TGF-beta1, was added in a similar manner to the culture. Results demonstrated that the characteristic bell- shaped growth response following treatment with increasing doses of DHT was converted to a linear dose-response curve as the growth of inhibition seen at the high dose by DHT was abolished. These observations, taken together, indicate that TGF-beta1 mediates at least in part the growth arrest observed at the high concentration of DHT in LNCaP cells.
 ...
PMID:Transforming growth factor-beta1 is a mediator of androgen-regulated growth arrest in an androgen-responsive prostatic cancer cell line, LNCaP. 860 13

Cytokeratin expression in normal and malignant prostatic tissue indicates a loss of basal epithelial cells in cancer. We investigated the ability of basal-like prostatic epithelial cells to inhibit the growth of prostatic cancer cells. Human prostate LNCaP cells were grown in medium with or without 10 nM dihydrotestosterone (DHT) on plastic culture dishes or on extracellular matrix derived from basal-like epithelial cells (primary cultures derived from normal peripheral zone of the prostate) that were grown with or without 10 nM DHT. Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays were used to assess the growth of LNCaP cells. On plastic dishes, growth of LNCaP cells was increased 5-10% by the presence of DHT in the medium. On matrix derived from basal-like cells that were grown in the absence of DHT, growth of LNCaP cells with or without DHT was similar to that on plastic. However, on matrix derived from basal-like cells that were grown with DHT, growth of LNCaP cells was suppressed when compared to all other culture conditions (P < 0.01). To determine whether basal-like cells could alter the function of LNCaP cells, we measured prostate-specific antigen (PSA) mRNA expression with the use of comparative RT-PCR. We found a significant decrease in the mature PSA transcript in cells grown on matrix derived from basal-like cells that were grown with DHT. The expression of PSA transcript was not altered in LNCaP cells that were grown on matrix derived from basal-like cells that were grown in the absence of DHT. Furthermore, using differential display of mRNA, we demonstrated that there were induction and suppression of multiple unique transcripts in the LNCaP cells when grown on the various culture conditions. To determine a possible mechanism for these observations. We used a dot blot immunoassay for several known inhibitory factors. We determined that DHT can induce the basal-like cells to secrete transforming growth factor-beta (TGF-beta 1), and that TGF-beta 1 can inhibit the proliferation of LNCaP cells in a dose dependent manner. We conclude that basal-like epithelial cells, in the presence of DHT, secrete an extracellular matrix o matrix associated factor(s), e.g. TGF-beta 1, that suppresses proliferation and function of prostate cancer cells. Our data suggest that the disappearance of the basal cell layer may be a prerequisite for the progression of prostatic neoplasia.
 ...
PMID:Role of prostatic basal cells in the regulation and suppression of human prostate cancer cells. 866 81

Prostate epithelial cell growth is under the control of both steroid and peptide factors. Human prostate cancer cell lines have been used to investigate similar agents in malignancy. Activins are dimeric peptides structurally related to transforming growth factor-beta and produced in the gonads and a wide array of extragonadal tissues. The activins act at the pituitary to regulate the synthesis and secretion of FSH. At other sites, such as bone marrow, liver, and gonads, activin may play an important role in the regulation of cell growth and differentiation. It was the purpose of the current study to determine whether activin had similar actions on prostate cancer cells, specifically the androgen-responsive LNCaP and the androgen-resistant PC-3 cell lines. Using reverse transcription-PCR, messenger RNAs for type I and type II activin receptor subunits as well as the activin-binding protein follistatin were detected in both cell lines. Activin treatment rapidly (<24 h) inhibited LNCaP, but not PC-3, cell growth. The effects of activin were evident at low levels, with a concentration of 5 ng/ml being effective at 24 h, and a concentration of 0.5 ng/ml being effective at 48 h. These results contrasted with the actions of transforming growth factor-beta, which inhibited only PC-3 cells and required a greater treatment duration (96 h) to be effective. To determine whether these prostate cancer cell lines were also producing activin, LNCaP and PC-3 cells were treated with follistatin. Again, only the LNCaP cells responded, with growth acceleration noted by 24 h. As PC-3 cell responses to activin could be independent of cell proliferation, we transfected LNCaP and PC-3 cells with a known activin-responsive promoter/reporter gene construct (p3TP-Lux) and treated cells with activin. Only LNCaP cells produced a measurable response in luciferase activity. Finally, we attempted to determine whether the PC-3 cell resistance to activin was mediated via a transferable factor. PC-3 conditioned medium was added to LNCaP cells in the absence or presence of exogenous activin and had a small, but statistically nonsignificant (P < 0.09), action to blunt the actions of activin. We conclude that activin is a potent growth inhibitor of LNCaP cell growth. Moreover, these cells also produce activin, suggesting that locally derived activin may play a role in regulating cell proliferation. Despite expressing messenger RNAs for activin receptors, PC-3 cells are resistant to activin, perhaps the result of the production of an activin-blocking factor or a defective activin response system. These cell lines will thus serve as useful models in which to further study the cellular basis of activin action.
 ...
PMID:Activin inhibition of prostate cancer cell growth: selective actions on androgen-responsive LNCaP cells. 894 Mar 39

Among the more interesting studies at the 1996 annual meeting of the American Society of Clinical Oncology that related to hormone-refractory prostate cancer were several that reported on the use of cis-retinoic acid both alone and in combination with interferon-alpha. Interferon-alpha and interferon-alpha plus cis-retinoic acid have antiproliferative effects in vitro against both PC3 and D-145 prostate cancer cells in culture. BCL2 expression is increased in androgen-independent cells, which may block apoptosis, and retinoids induce transforming growth factor-beta and apoptosis in prostate cancer cell lines. This regimen raises many questions. For example, it is difficult to determine what prostate-specific antigen (PSA) level one should expect from cis-retinoic acid, 4HPR, or any of the other differentiating agents. Should there be an increase in PSA1 Should one expect a slower decline in PSA when giving additional agents that are in fact cytotoxic? What is the significance of a changing level of PSA after this and other types of treatment? These and other questions remain to be determined in future studies.
 ...
PMID:Highlights of abstracts on hormone-refractory prostate cancer presented at the 1996 annual meeting of the American Society of Clinical Oncology. 899 77

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is known to block IGF action and inhibit cell growth. IGFBP-3 is thought to act by sequestering free IGFs or, possibly, act via a novel IGF-independent mechanism. Supporting its role as a primary growth inhibitor, IGFBP-3 production has been shown to be increased by cell growth-inhibitory agents, such as transforming growth factor-beta (TGF-beta), and the tumor suppressor gene p53. In this paper, we demonstrate, for the first time, a novel function of IGFBP-3 as an apoptosis-inducing agent and show that this action is mediated through an IGF.IGF receptor-independent pathway. In the p53 negative prostate cancer cell line, PC-3, the addition of recombinant IGFBP-3 resulted in a dose-dependent induction of apoptosis. 125I-IGFBP-3 bound with high affinity to specific proteins in PC-3 cell lysates and plasma membrane preparations. These membrane-associated molecules may serve as receptors that mediate the direct effect of IGFBP-3 on apoptosis. In addition, in an IGF receptor-negative mouse fibroblast cell line, treatment with recombinant IGFBP-3 as well as transfection of the IGFBP-3 gene induced apoptosis, suggesting that neither IGFs nor IGF receptors are required for this action. Furthermore, treatment with TGF-beta1, a known apoptosis-inducing agent, resulted in the induction of IGFBP-3 expression 6-12 h before the onset of apoptosis. This effect of TGF-beta1 was prevented by co-treatment with IGFBP-3-neutralizing antibodies or IGFBP-3-specific antisense thiolated oligonucleotides. These findings suggest that IGFBP-3 induces apoptosis through a novel pathway independent of either p53 or the IGF.IGF receptor-mediated cell survival pathway and that IGFBP-3 mediates TGF-beta1 induced apoptosis in PC-3 cells.
 ...
PMID:Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism. 911 91

This review focuses on the possible role of transforming growth factor-beta isoforms 1-3 (TGFbeta) in prostate cancer. TGFbeta1 appears to inhibit the cellular proliferation of normal prostate cells. Surprisingly, TGFbeta1 is overexpressed in prostate cancer. To help explain this apparent paradox, it has been revealed that with tumor progression, prostate cancer cells acquire reduced sensitivity to the growth-inhibitory effects of TGFbeta1. Aberrations of the TGFbeta1 signaling pathway at the prereceptor, receptor, or postreceptor level may lead to prostate cancer cell resistance to TGFbeta1 growth inhibition. Indirectly, elevated levels of TGFbeta1 may induce host effects that may be beneficial to prostate tumor growth by suppressing the immune system, promoting angiogenesis and extracellular matrix formation, and enhancing metastatic potential. Consequently, TGFbeta1 appears to be important in prostate carcinogenesis and tumorigenicity. TGFbeta2 and TGFbeta3 are only briefly presented as very little is known about their role in prostate cancer.
 ...
PMID:Transforming growth factor-beta and prostate cancer. 911 51

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGF-beta) family and have been identified as factors that stimulate bone formation in vivo. They turned out to be multifunctional molecules regulating the growth, differentiation, and apoptosis in various target cells. Some BMPs and their receptors (BMPRs) are expressed on prostate cancer cells. We have reported previously that BMPR-IB mRNA expression is highest in the prostate, a characteristic that is not shared by the other BMPRs, BMPR-IA and BMPR-II. However, the amounts of BMPR-IB mRNA were significantly low in prostate tissues after androgen withdrawal therapy. They were also low in prostate cancer cell lines. Semiquantitative RT-PCR showed that BMPR-IB mRNA was induced by androgen in the androgen-sensitive human prostatic cancer cell line LNCaP, whereas the expression of BMPR-IA and BMPR-II mRNAs was not affected by androgen. When the recombinant human BMP-2 was added to the LNCaP cells in the presence of androgen, cell growth was inhibited. In contrast, the growth rate was increased by the addition of the same ligand when the cells were cultured in the absence of androgen; under this condition, the amounts of BMPR-IB mRNA were decreased significantly. These observations showed that the amounts of BMPR-IB, but not those of BMPR-IA, were regulated by androgen and further suggest that BMPR-IA and BMPR-IB differentially modulate prostate cancer cell growth in response to BMP under different hormonal conditions; BMPR-IA elicits growth stimulation, and BMPR-IB conveys a negative regulatory signal in response to BMP-2.
 ...
PMID:Growth regulation of human prostate cancer cells by bone morphogenetic protein-2. 937 96


1 2 3 4 5 6 7 8 Next >>