Novel Role of Androgens in Mitochondrial Fission and Apoptosis

Abstract

Androgen and androgen receptors (AR) play critical roles in the proliferation of prostate cancer through transcriptional regulation of target genes. Here, we found that androgens upregulated the expression of dynamin-related protein 1 (Drp1), which is involved in the induction of mitochondrial fission (MF), a common event in mitosis and apoptosis. Clinical tissue samples and various prostate cancer cell lines revealed a positive correlation between Drp1 and AR levels. Treatment of androgen-sensitive cells with an AR agonist, R1881, and antagonist, bicalutamide, showed that Drp1 is transcriptionally regulated by androgens, as confirmed by an AR ChIP-chip assay. Live imaging experiments using pAcGFP1-Mito stably transfected LNCaP (mito-green) cells revealed that androgen did not induce significant MF by itself, although Drp1 was upregulated. However, when treated with CGP37157 (CGP), an inhibitor of mitochondrial Ca2+ efflux, these cells exhibited MF, which was further enhanced by pre-treatment with R1881, suggesting that androgen-induced Drp1 facilitated CGP-induced MF. This enhanced MF was correlated with increased apoptosis. Transfection with DN-Drp1 (K38A) rescued cells from increased apoptosis, confirming the role of androgen-induced Drp1 in the observed apoptosis with combination treatment. Further, we found that CGP reduced the expression of Mfn1, a protein that promotes mitochondrial fusion, a process which opposes fission. We suggest that androgen-increased Drp1 enhanced MF leading to apoptosis. The present study demonstrates a novel role for androgens in the regulation of mitochondrial morphology that could potentially be utilized in prostate cancer therapy.