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



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.



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.



Restoration of mitochondrial function may provide new option for reducing PCa health disparity among American men.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Ajay K
AK
Chaudhary
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Tariq A
TA
Bhat
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Sandeep
S
Kumar
NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Anil
A
Kumar
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Rahul
R
Kumar
Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Willie
W
Underwood
Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.|Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Shahriar
S
Koochekpour
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Mojgan
M
Shourideh
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Neelu
N
Yadav
NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Shanta
S
Dhar
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Dhyan
D
Chandra
D001741:Black or African American; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000208:ethnology* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014481:United States
D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D003999:Dichloroacetic Acid