Mitochondrial dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African-American men with prostate cancer

Ajay K. Chaudhary, Tariq A. Bhat, Sandeep Kumar, Anil Kumar, Rahul Kumar, Willie Underwood, Shahriar Koochekpour, Mojgan Shourideh, Neelu Yadav, Shanta Dhar, Dhyan Chandra

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Background:African-American (AA) patients with prostate cancer (PCa) respond poorly to current therapy compared with Caucasian American (CA) PCa patients. Although underlying mechanisms are not defined, mitochondrial dysfunction is a key reason for this disparity.Methods:Cell death, cell cycle, and mitochondrial function/stress were analysed by flow cytometry or by Seahorse XF24 analyzer. Expression of cellular proteins was determined using immunoblotting and real-time PCR analyses. Cell survival/motility was evaluated by clonogenic, cell migration, and gelatin zymography assays.Results:Glycolytic pathway inhibitor dichloroacetate (DCA) inhibited cell proliferation in both AA PCa cells (AA cells) and CA PCa cells (CA cells). AA cells possess reduced endogenous reactive oxygen species, mitochondrial membrane potential (mtMP), and mitochondrial mass compared with CA cells. DCA upregulated mtMP in both cell types, whereas mitochondrial mass was significantly increased in CA cells. DCA enhanced taxol-induced cell death in CA cells while sensitising AA cells to doxorubicin. Reduced expression of heat shock proteins (HSPs) was observed in AA cells, whereas DCA induced expression of CHOP, C/EBP, HSP60, and HSP90 in CA cells. AA cells are more aggressive and metastatic than CA cells.Conclusions:Restoration of mitochondrial function may provide new option for reducing PCa health disparity among American men.

Original languageEnglish (US)
Pages (from-to)1090-1100
Number of pages11
JournalBritish Journal of Cancer
Volume114
Issue number10
DOIs
StatePublished - May 10 2016
Externally publishedYes

Keywords

  • apoptosis
  • dichloroacetate
  • mitochondrial dysfunction
  • oxidative phosphorylation
  • reactive oxygen species

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chaudhary, A. K., Bhat, T. A., Kumar, S., Kumar, A., Kumar, R., Underwood, W., Koochekpour, S., Shourideh, M., Yadav, N., Dhar, S., & Chandra, D. (2016). Mitochondrial dysfunction-mediated apoptosis resistance associates with defective heat shock protein response in African-American men with prostate cancer. British Journal of Cancer, 114(10), 1090-1100. https://doi.org/10.1038/bjc.2016.88