RT Journal Article
SR Electronic
T1 Novel Role of Androgens in Mitochondrial Fission and Apoptosis
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
SP 1067
OP 1077
DO 10.1158/1541-7786.MCR-10-0445
VO 9
IS 8
A1 Choudhary, Vivek
A1 Kaddour-Djebbar, Ismail
A1 Lakshmikanthan, Vijayabaskar
A1 Ghazaly, Taghreed
A1 Thangjam, Gagan Singh
A1 Sreekumar, Arun
A1 Lewis, Ronald W.
A1 Mills, Ian G.
A1 Bollag, Wendy B.
A1 Kumar, M. Vijay
YR 2011
UL http://mcr.aacrjournals.org/content/9/8/1067.abstract
AB 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, 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-seq assay. Live imaging experiments using pAcGFP1-Mito stably transfected LNCaP (mito-green) cells revealed that androgen did not induce significant mitochondrial fission by itself, although Drp1 was upregulated. However, when treated with CGP37157 (CGP), an inhibitor of mitochondrial Ca2+ efflux, these cells exhibited mitochondrial fission, which was further enhanced by pretreatment with R1881, suggesting that androgen-induced Drp1 expression facilitated CGP-induced mitochondrial fission. This enhanced mitochondrial fission was correlated with increased apoptosis. Transfection with dominant-negative (DN-Drp1, K38A) rescued cells from increased apoptosis, confirming the role of androgen-induced Drp1 in the observed apoptosis with combination treatment. Furthermore, 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 mitochondrial fission leading to apoptosis. The present study shows a novel role for androgens in the regulation of mitochondrial morphology that could potentially be utilized in prostate cancer therapy. Mol Cancer Res; 9(8); 1067–77. ©2011 AACR.