Document Detail


Novel role of androgens in mitochondrial fission and apoptosis.
MedLine Citation:
PMID:  21724752     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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
Descriptor/Qualifier:
Androgens / metabolism*,  physiology
Apoptosis
Cell Line, Tumor
Cell Proliferation
GTP Phosphohydrolases / genetics,  metabolism*
Gene Expression Regulation, Neoplastic
Humans
Male
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
ID/Acronym/Agency:
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
Chemical
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 3.6.5.5/DNM1L protein, human
Comments/Corrections

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


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