The role of Bak-mediated dissipation of mitochondrial membrane potential in radiosensitivity of Bax-negative human prostate cancer cells

Abstract

In the radiotherapy of localised cancers, susceptibility of tumour and normal cells to undergo radiation-induced programmed cell death is an important prognostic factor. Mitochondria-mediated cell death is often preceded by dissipation of mitochondrial membrane potential. This study investigates whether human prostate cancer cells would preferentially die via the mitochondria-mediated pathway after photon and neutron irradiation. Bax-negative human prostate cancer cells were irradiated with p(66)/Be neutrons or 60Co -rays, in the absence or presence of an inhibitor of Bak translocation to mitochondria. Dissipation of mitochondrial membrane potential was assessed using the DePsipherTM kit. Cell survival was assessed using the colony forming assay. The dose response for the dissipation of mitochondria membrane potential was clearly dependent on radiation type, and the presence of the Bak inhibitor during irradiation almost completely abolished this process. This was paralleled by a significant enhancement in radioresistance in the presence of the inhibitor. These data indicate that, in Bax-negative tumours, Bak availability may lead to significant increases in the radiosensitivity, and can result in an enhanced therapeutic benefit. Keywords: prostate cancer; radiotherapy; mitochondrial membrane potential; Bak