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

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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 (US)
Pages (from-to)1067-1077
Number of pages11
JournalMolecular Cancer Research
Volume9
Issue number8
DOIs
StatePublished - Aug 1 2011

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Mitochondrial Dynamics
Dynamins
Androgens
Apoptosis
Proteins
Androgen Receptors
Metribolone
Prostatic Neoplasms
Androgen Receptor Antagonists
Mitosis
Transfection

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Choudhary, V., Kaddour-Djebbar, I., Lakshmikanthan, V., Ghazaly, T., Thangjam, G. S., Sreekumar, A., ... Kumar, M. V. (2011). Novel role of androgens in mitochondrial fission and apoptosis. Molecular Cancer Research, 9(8), 1067-1077. https://doi.org/10.1158/1541-7786.MCR-10-0445

Novel role of androgens in mitochondrial fission and apoptosis. / Choudhary, Vivek; Kaddour-Djebbar, Ismail; Lakshmikanthan, Vijayabaskar; Ghazaly, Taghreed; Thangjam, Gagan Singh; Sreekumar, Arun; Lewis, Ronald W; Mills, Ian G.; Bollag, Wendy B; Kumar, M. Vijay.

In: Molecular Cancer Research, Vol. 9, No. 8, 01.08.2011, p. 1067-1077.

Research output: Contribution to journalArticle

Choudhary, V, Kaddour-Djebbar, I, Lakshmikanthan, V, Ghazaly, T, Thangjam, GS, Sreekumar, A, Lewis, RW, Mills, IG, Bollag, WB & Kumar, MV 2011, 'Novel role of androgens in mitochondrial fission and apoptosis', Molecular Cancer Research, vol. 9, no. 8, pp. 1067-1077. https://doi.org/10.1158/1541-7786.MCR-10-0445
Choudhary V, Kaddour-Djebbar I, Lakshmikanthan V, Ghazaly T, Thangjam GS, Sreekumar A et al. Novel role of androgens in mitochondrial fission and apoptosis. Molecular Cancer Research. 2011 Aug 1;9(8):1067-1077. https://doi.org/10.1158/1541-7786.MCR-10-0445
Choudhary, Vivek ; Kaddour-Djebbar, Ismail ; Lakshmikanthan, Vijayabaskar ; Ghazaly, Taghreed ; Thangjam, Gagan Singh ; Sreekumar, Arun ; Lewis, Ronald W ; Mills, Ian G. ; Bollag, Wendy B ; Kumar, M. Vijay. / Novel role of androgens in mitochondrial fission and apoptosis. In: Molecular Cancer Research. 2011 ; Vol. 9, No. 8. pp. 1067-1077.
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