Translational Therapeutics

BJC Open article

British Journal of Cancer (2016) 114, 1090–1100. doi:10.1038/bjc.2016.88 www.bjcancer.com
Published online 26 April 2016

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

Ajay K Chaudhary1,5, Tariq A Bhat1,5, Sandeep Kumar1, Anil Kumar2, Rahul Kumar1, Willie Underwood3, Shahriar Koochekpour3,4, Mojgan Shourideh4, Neelu Yadav1, Shanta Dhar2 and Dhyan Chandra1

  1. 1Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
  2. 2NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, USA
  3. 3Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
  4. 4Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

Correspondence: Dr D Chandra, E-mail: dhyan.chandra@roswellpark.org

5These authors contributed equally to this work.

Revised 10 March 2016; Accepted 10 March 2016
Advance online publication 26 April 2016

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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.

Keywords:

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