Aspirin Induces Mitochondrial Ca Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca Entry.

Aspirin (acetylsalicylic acid) and its metabolite salicylate, have an anti-melanoma effect by evoking mitochondrial dysfunction through poorly understood mechanisms. Depolarization of the plasma membrane potential leads to voltage-gated Ca entry (VGCE) and caspase-3 activation. In the present study, we investigated the role of depolarization and VGCE in aspirin's anti-melanoma effect. Aspirin and to a lesser extent, salicylate (≥2.5 mM) induced a rapid (within seconds) depolarization, while they caused comparable levels of depolarization with a lag of 2~4 h. Reactive oxygen species (ROS) generation also occurred in the two-time points, and antioxidants abolished the early ROS generation and depolarization. At the same concentrations, the two drugs induced apoptotic and necrotic cell death in a caspase-independent manner, and antioxidants and Ca channel blockers prevented cell death. Besides ROS generation, reduced mitochondrial Ca (Ca) and mitochondrial membrane potential preceded cell death. Moreover, the cells expressed the Ca1.2 isoform of l-type Ca channel, and knockdown of Ca1.2 abolished the decrease in Ca. Our findings suggest that aspirin and salicylate induce Ca remodeling, mitochondrial dysfunction, and cell death via ROS-dependent depolarization and VGCE activation.