Document Detail

Novel role of androgens in mitochondrial fission and apoptosis.
MedLine Citation:
PMID:  21724752     Owner:  NLM     Status:  MEDLINE    
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.
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-07-01
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  9     ISSN:  1557-3125     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-17     Completed Date:  2011-12-14     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1067-77     Citation Subset:  IM    
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MeSH Terms
Androgens / metabolism*,  physiology
Cell Line, Tumor
Cell Proliferation
GTP Phosphohydrolases / genetics,  metabolism*
Gene Expression Regulation, Neoplastic
Metribolone / metabolism
Microtubule-Associated Proteins / genetics,  metabolism*
Mitochondria / metabolism*,  physiology
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Proteins / genetics,  metabolism*
Prostatic Neoplasms / metabolism*,  pathology
Receptors, Androgen / genetics,  metabolism*
Grant Support
1R03CA139489-01/CA/NCI NIH HHS; R01 CA133458/CA/NCI NIH HHS; R01 CA133458-03/CA/NCI NIH HHS; R01 CA133458-04/CA/NCI NIH HHS; R01CA133458-04/CA/NCI NIH HHS; R03 CA139489/CA/NCI NIH HHS; R03 CA139489-02/CA/NCI NIH HHS; RC1 CA145444/CA/NCI NIH HHS; RC1 CA145444-01/CA/NCI NIH HHS; RCA145444A//PHS HHS
Reg. No./Substance:
0/AR protein, human; 0/Androgens; 0/Microtubule-Associated Proteins; 0/Mitochondrial Membrane Transport Proteins; 0/Mitochondrial Proteins; 0/Receptors, Androgen; 2C323EGI97/Metribolone; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.5.-/Mfn1 protein, human; EC protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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