MECHANISMS OF MITOCHONDRIA-MEDIATED APOPTOSIS INDUCED BY CYTOTOXIC STRESS

Abstract

Defects within the apoptotic pathway are thought to contribute to tumorigenesis and therapeutic resistance. Although most cytotoxic anti-cancer drugs are thought to activate the mitochondria-mediated apoptotic pathway, the precise mechanistic details remain unclear and, in some instances, controversial. We investigated the underlying molecular requirements necessary for mitochondria-mediated apoptosis induced by a DNA topoisomerase II inhibitor, a novel heat shock protein 90 (Hsp90) inhibitor, and elevated temperature in Jurkat T-lymphocytes. The data suggest that irreversible commitment to apoptosis induced by DNA-damage and heat-shock relies on a feed forward amplification loop of the initial death signal that is mediated by effector caspases and mitochondria. However, the pathway leading to cell death by inhibition of Hsp90 appeared to be in line with the traditional linear perspective of mitochondria-mediated apoptosis. Combined, the data suggest that different cytotoxic stressors use similar as well as distinct mechanisms to execute mitochondria-mediated apoptosis.