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Androgens promote prostate cancer cell growth through induction of autophagy.

ABSTRACT: Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases. However, the mechanisms by which androgens exert their regulatory activities on these processes are poorly understood. In this study, we have determined that androgens regulate overall cell metabolism and cell growth, in part, by increasing autophagy in prostate cancer cells. Importantly, inhibition of autophagy using either pharmacological or molecular inhibitors significantly abrogated androgen-induced prostate cancer cell growth. Mechanistically, androgen-mediated autophagy appears to promote cell growth by augmenting intracellular lipid accumulation, an effect previously demonstrated to be necessary for prostate cancer cell growth. Further, autophagy and subsequent cell growth is potentiated, in part, by androgen-mediated increases in reactive oxygen species. These findings demonstrate a role for increased fat metabolism and autophagy in prostatic neoplasias and highlight the potential of targeting underexplored metabolic pathways for the development of novel therapeutics.

SUBMITTER: Shi Y

PROVIDER: S-EPMC3683804 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Androgens promote prostate cancer cell growth through induction of autophagy.

Shi Yan Y Han Jenny J JJ Tennakoon Jayantha B JB Mehta Fabiola F FF Merchant Fatima A FA Burns Alan R AR Howe Matthew K MK McDonnell Donald P DP Frigo Daniel E DE

Molecular endocrinology (Baltimore, Md.) 20121218 2

Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases. However, the mechanisms by which androgens exert their regulatory activities on these processes are poorly understood. In this study, we have determined that androgens regulate overall cell metabolism and cell growth, in part, by increasing autophagy in prostate cancer cells. Importantly, inhibition of autophagy using either pharmacological or molecular inhibitors significantly abrogate ...[more]

PMID: 23250485

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Project description:Patients with metastatic prostate cancer frequently develop bone metastases that elicit significant skeletal morbidity and increased mortality. The high tropism of prostate cancer cells for bone and their tendency to induce the osteoblastic-like phenotype are a result of a complex interplay between tumor cells and osteoblasts. Although the role of osteoblasts in supporting prostate cancer cell proliferation has been reported by previous studies, their precise contribution in tumor growth remains to be fully elucidated. Here, we tried to dissect the molecular signaling underlining the interactions between castration-resistant prostate cancer (CRPC) cells and osteoblasts using in vitro co-culture models. Transcriptomic analysis showed that osteoblast-conditioned media (OCM) induced the overexpression of genes related to cell cycle in the CRPC cell line C4-2B but, surprisingly, reduced androgen receptor (AR) transcript levels. In-depth analysis of AR expression in C4-2B cells after OCM treatment showed an AR reduction at the mRNA (p = 0.0047), protein (p = 0.0247), and functional level (p = 0.0029) and, concomitantly, an increase of C4-2B cells in S-G2-M cell cycle phases (p = 0.0185). An extensive proteomic analysis revealed in OCM the presence of some molecules that reduced AR activation, and among these, Matrix metalloproteinase-1 (MMP-1) was the only one able to block AR function (0.1 ng/ml p = 0.006; 1 ng/ml p = 0.002; 10 ng/ml p = 0.0001) and, at the same time, enhance CRPC proliferation (1 ng/ml p = 0.009; 10 ng/ml p = 0.033). Although the increase of C4-2B cell growth induced by MMP-1 did not reach the proliferation levels observed after OCM treatment, the addition of Vorapaxar, an MMP-1 receptor inhibitor (Protease-activated receptor-1, PAR-1), significantly reduced C4-2B cell cycle (0.1 μM p = 0.014; 1 μM p = 0.0087). Overall, our results provide a novel AR-independent mechanism of CRPC proliferation and suggest that MMP-1/PAR-1 could be one of the potential pathways involved in this process.

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Androgens promote prostate cancer cell growth through induction of autophagy.

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Androgens promote prostate cancer cell growth through induction of autophagy.

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