Inhibition of growth and induction of apoptosis by androgens of a variant of LNCaP cell line

Joly-Pharaboz, Marie-Odile; Ruffion, A.; Roch, Anne-Marie; Michel-Calemard, Laurence; André, Jean; Chantepie, Jacqueline; Nicolas, Brigitte; Panaye, Geneviève

doi:10.1016/s0960-0760(00)00076-5

Cited by 48 publications

(46 citation statements)

References 25 publications

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“…Because AR protein is overexpressed in advanced prostate cancer, increased AR signaling may contribute to tumor progression and emergence of the hormone-independent phenotype (39). However, studies on the LNCaP cell line indicate that although low-level activation of (albeit mutated) AR can facilitate cell growth, hyperactivation can lead to cell death (40), consistent with our hypothesis that AR has properties consistent with a tumor suppressor and that abrogation of AR action is associated with proliferative disease. This is reminiscent of the case of p53.…”

Section: Discussionsupporting

confidence: 87%

Mutation of the androgen receptor causes oncogenic transformation of the prostate

Han

Buchanan

Ittmann

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

120

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Recent evidence demonstrates that the androgen receptor (AR) continues to influence prostate cancer growth despite medical therapies that reduce circulating androgen ligands to castrate levels and͞or block ligand binding. Whereas the mutation, amplification, overexpression of AR, or cross-talk between AR and other growth factor pathways may explain the failure of androgen ablation therapies in some cases, there is little evidence supporting a causal role between AR and prostate cancer. In this study, we functionally and directly address the role whereby AR contributes to spontaneous cancer progression by generating transgenic mice expressing (i) AR-WT to recapitulate increased AR levels and ligand sensitivity, (ii) AR-T857A to represent a promiscuous AR ligand response, and (iii) AR-E231G to model altered AR function. Whereas transgenes encoding either AR-WT or AR-T857A did not cause prostate cancer when expressed at equivalent levels, expression of AR-E231G, which carries a mutation in the most highly conserved signature motif of the NH 2-terminal domain that also influences interactions with cellular coregulators, caused rapid development of prostatic intraepithelial neoplasia that progressed to invasive and metastatic disease in 100% of mice examined. Taken together, our data now demonstrate the oncogenic potential of steroid receptors and implicate altered AR function and receptor coregulator interaction as critical determinants of prostate cancer initiation, invasion, and metastasis.

show abstract

Section: Discussionsupporting

confidence: 87%

Mutation of the androgen receptor causes oncogenic transformation of the prostate

Han

Buchanan

Ittmann

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

173

120

View full text Add to dashboard Cite

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“…The role of the male steroid hormone androgen in apoptosis of androgen-independent prostate cancer cells is highly controversial, being suggested to have an antiapoptotic or proapoptotic role (25,31,50,61). It has been reported that androgen induces apoptosis in AR-expressing PC3 cells (25).…”

Section: Discussionmentioning

confidence: 99%

“…However, the role of androgen in apoptosis of androgen-independent prostate cancer cells is controversial, being suggested to be proapoptotic or antiapoptotic (25,31,50,61). Considering that in vivo a low amount of androgen is still produced even after castration, a paradox is whether androgen is beneficial or detrimental to the treatment of malignant prostate cancer.…”

mentioning

confidence: 99%

Androgen and Its Receptor Promote Bax-Mediated Apoptosis

Lin

Kokontis

Tang

et al. 2006

Molecular and Cellular Biology

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Androgen and its receptor (AR) have been reported to have pro-or antiapoptotic functions. However, the underlying molecular mechanism is incompletely understood. We report here that androgen and AR promote Bax-mediated apoptosis in prostate cancer cells. UV irradiation and ectopic expression of Bax induce apoptosis in AR-positive, but not AR-negative prostate cancer cells. UV-and Bax-induced apoptosis is abrogated in AR-positive cells that express small interference RNA (siRNA) of AR and is sensitized by reintroduction of AR into AR-negative cells. Although AR is able to promote Bax-mediated apoptosis independently of androgen, the promotion by AR can be further potentiated by androgen via AR-dependent transcription activation. AR is essential for the translocation of Bax to mitochondria in UV-or Bax-induced apoptosis. Inhibition of Bax expression by Bax siRNA suppresses UV-induced apoptosis in AR-positive cells. In addition, introduction of AR into AR-negative prostate cancer cells upregulates expression levels of the BH3-only protein Noxa, whereas inhibition of Noxa expression reduces the promotion by AR on UV-induced apoptosis. Thus, our results reveal a novel cross talk between the androgen/AR hormonal signaling pathway and the intrinsic apoptotic death pathway that determines the sensitivity of stress-induced apoptosis in prostate cancer cells.

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“…On the other hand, steroid hormones have well-documented stimulatory and inhibitory effects on target cell proliferation. These effects are steroid- and target cell-specific and are mediated by cell cycle phase-specific actions [7, 8]. …”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has also been suggested that androgens could paradoxically repress the growth of some prostate cancer cells both in culture and in vivo [7]. In the human prostate cancer cell line, LNCaP, and in variants derived from it, the addition of androgens at low physiological concentrations results in increased proliferation rates, while at high physiological concentrations androgens induce proliferative shutoff [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Androgen-Dependent Expression of <i>c-jun</i> and <i>c-fos</i> in Human Non-Transformed Epithelial Prostatic Cells: Association with Cell Proliferation

et al. 2003

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Objective: To assess the effect of dihydrotestosterone (DHT) on the gene expression of c-fos and c-jun and on the proliferation of human non-transformed epithelial prostatic (HNTEP) cells. Methods: Cell proliferation (MTT) and c-fos and c-jun mRNA expression (RT-PCR) were determined in cells treated with DHT (10^–8, 10^–10, and 10^–13M) or with control medium. Results: DHT 10^–13 M had a significant stimulatory effect on cell proliferation (p < 0.05) and c-fos and c-jun gene expression when compared to cells treated with higher concentrations of this hormone (10^–10 and 10^–8M) or with the control group. Conclusions: Our data demonstrate that the increase in c-fos and c-jun expression and cell growth in HNTEP cells is maximal with the lowest DHT concentration (10^–13M). These proto-oncogenes may play a role in the control of hormone responsiveness and cell proliferation in HNTEP cells.

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Inhibition of growth and induction of apoptosis by androgens of a variant of LNCaP cell line

Cited by 48 publications

References 25 publications

Mutation of the androgen receptor causes oncogenic transformation of the prostate

Mutation of the androgen receptor causes oncogenic transformation of the prostate

Androgen and Its Receptor Promote Bax-Mediated Apoptosis

Androgen-Dependent Expression of <i>c-jun</i> and <i>c-fos</i> in Human Non-Transformed Epithelial Prostatic Cells: Association with Cell Proliferation

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