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Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity.

ABSTRACT: Edelfosine is a synthetic alkyl-lysophospholipid that possesses significant antitumor activity in several human tumor models. Here, we investigated the effects of edelfosine combined with androgen deprivation (AD) in LNCaP and VCaP human prostate cancer cells. This treatment regimen greatly decreased cell proliferation compared with single agent or AD alone, resulting in higher levels of apoptosis in LNCaP compared with VCaP cells. Edelfosine caused a dose-dependent decrease in AKT activity, but did not affect the expression of total AKT in either cell line. Furthermore, edelfosine treatment inhibited the expression of androgen receptor (AR) and was associated with an increase in activating transcription factor 3 (ATF3) expression levels, a stress response gene and a negative regulator of AR transactivation. ATF3 binds to AR after edelfosine + AD and represses the transcriptional activation of AR as demonstrated by PSA promoter studies. Knockdown of ATF3 using siRNA-ATF3 reversed the inhibition of PSA promoter activity, suggesting that the growth inhibition effect of edelfosine was ATF3 dependent. Moreover, expression of AR variant 7 (ARv7) and TMPRSS2-ERG fusion gene were greatly inhibited after combined treatment with AD and edelfosine in VCaP cells. In vivo experiments using an orthotopic LNCaP model confirmed the antitumor effects of edelfosine + AD over the individual treatments. A significant decrease in tumor volume and PSA levels was observed when edelfosine and AD were combined, compared with edelfosine alone. Edelfosine shows promise in combination with AD for the treatment of prostate cancer patients. Mol Cancer Ther; 15(6); 1353-63. ©2016 AACR.

SUBMITTER: Udayakumar TS

PROVIDER: S-EPMC4933508 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity.

Udayakumar Thirupandiyur S TS Stoyanova Radka R Shareef Mohammed M MM Mu Zhaomei Z Philip Sakhi S Burnstein Kerry L KL Pollack Alan A

Molecular cancer therapeutics 20160304 6

Edelfosine is a synthetic alkyl-lysophospholipid that possesses significant antitumor activity in several human tumor models. Here, we investigated the effects of edelfosine combined with androgen deprivation (AD) in LNCaP and VCaP human prostate cancer cells. This treatment regimen greatly decreased cell proliferation compared with single agent or AD alone, resulting in higher levels of apoptosis in LNCaP compared with VCaP cells. Edelfosine caused a dose-dependent decrease in AKT activity, but ...[more]

PMID: 26944919

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Project description:BackgroundCastration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells.ResultsTreatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.ConclusionsCollectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.

Project description:Prostate cancers (PCs), initially responsive to anti-androgen therapies, often advance to a hormone-refractory 'castrate-resistant' PC (CRPC) stage. However, the androgen receptor (AR) pathway remains active and key for cell growth and gene expression within tumours, even in the apparent absence of hormone. Proposed mechanisms to explain progression, including AR amplification/mutation, are insufficient to completely explain CRPC and possible roles of AR cofactors such as prohibitin (PHB) are poorly understood. We investigated whether PHB loss could sensitise PC cells and tumours to adrenal gland-derived androgens, which persist even after androgen ablation, hence contribute to development of CRPC. Using a pair of PC cell lines, inducibly expressing ectopic cDNA or RNAi for PHB, responses to different androgens and hormone concentrations were studied both in vitro and in vivo. PHB was found at the promoters of several genes, both AR and non-AR-regulated, and knockdown increased histone acetylation at these promoters. Further, PHB knockdown increased the rate of AR ligand-induced chromatin binding, and binding rate and occupancy of AR upon the PSA promoter. This resulted in increased cell growth and AR activity in response to all androgens, including promoting a response to the weaker adrenal androgens previously absent at physiological concentrations. In vivo this had functional consequences such that PHB knockdown resulted in androstenedione being sufficient to promote tumour growth, under conditions mimicking those in patients undergoing androgen ablation therapy. We conclude that reduction in PHB levels is sufficient to lower the threshold of AR activity in vitro and in vivo; this may be via a general increase in histone acetylation that could potentially affect signalling by other transcription factors. PHB loss may provide a mechanism for progression to CRPC by sensitising PC cells to 'castrate' conditions-that is, low levels of testicular androgens in the continued presence of weak adrenal and dietary androgens.

Dataset Information

Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity.

Publications

Edelfosine Promotes Apoptosis in Androgen-Deprived Prostate Tumors by Increasing ATF3 and Inhibiting Androgen Receptor Activity.

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