Novel role of androgens in mitochondrial fission and apoptosis

Vivek Choudhary, Ismail Kaddour-Djebbar, Vijayabaskar Lakshmikanthan, Taghreed Ghazaly, Gagan Singh Thangjam, Arun Sreekumar, Ronald W Lewis, Ian G Mills, Wendy B Bollag, M Vijay Kumar

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1067-77
Number of pages11
JournalMolecular cancer research : MCR
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 2011

Keywords

  • Androgens
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • GTP Phosphohydrolases
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Metribolone
  • Microtubule-Associated Proteins
  • Mitochondria
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Prostatic Neoplasms
  • Receptors, Androgen

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