title: 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, 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.
authors: Charlie Norwood VA Medical Center, Georgia Health Sciences University, Augusta, Georgia, USA.
authors: Vivek
authors: V
authors: Choudhary
authors: Ismail
authors: I
authors: Kaddour-Djebbar
authors: Vijayabaskar
authors: V
authors: Lakshmikanthan
authors: Taghreed
authors: T
authors: Ghazaly
authors: Gagan Singh
authors: GS
authors: Thangjam
authors: Arun
authors: A
authors: Sreekumar
authors: Ronald W
authors: RW
authors: Lewis
authors: Ian G
authors: IG
authors: Mills
authors: Wendy B
authors: WB
authors: Bollag
authors: M Vijay
authors: MV
authors: Kumar
mesh_terms: D000728:Androgens / Q000378:metabolism* / Q000502:physiology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D015741:Metribolone / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000728:Androgens; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011944:Receptors, Androgen; D015741:Metribolone; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins