Knockdown of iPLA₂γ enhances cisplatin-induced apoptosis by increasing ROS-dependent peroxidation of mitochondrial...

Cisplatin (CDDP) is a platinum-based drug with anti-cancer activity and is widely used as a standard therapy for bladder cancer. It is well known that CDDP causes cell death by increasing the generation of reactive oxygen species (ROS) and lipid peroxidation, but the mechanism of its anti-cancer effects has not been fully elucidated. There are still some problems such as chemoresistance in CDDP therapy. In the present study, we found the expression of Ca²⁺-independent phospholipase A₂γ (iPLA₂γ), which has been reported to regulate cellular redox homeostasis by inhibiting lipid peroxide accumulation, in human bladder cancer tissues. Thus, we investigated the effect of iPLA₂γ knockdown on CDDP-induced bladder cancer cell death. As a result, we found that iPLA₂γ knockdown significantly enhanced CDDP-induced apoptosis, intracellular and mitochondrial ROS production, cytochrome c release and caspase activation in bladder cancer cells. Moreover, mitochondrial membrane potential was decreased and peroxidation of mitochondrial phospholipids was increased by iPLA₂γ knockdown. It was also shown that co-treatment of bromoenol lactone, an iPLA₂ inhibitor, increased CDDP-induced apoptosis. These results indicated that iPLA₂γ plays an important role in protecting bladder cancer cells from CDDP-induced apoptosis, and that iPLA₂γ inhibitors might represent a novel strategy in CDDP-based multi-drug therapy.