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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is promisingfor cancer treatment owing to its selective cytotoxicity against malignant cells.However, some cancer cell types, including malignant melanoma cells, are resistantto TRAIL-induced apoptosis. Therefore, drugs that can amplify TRAIL cytotoxicityare urgently required. Depolarization of the plasma membrane potential is associatedwith apoptosis induced by a variety of death-inducing agents but its role in apoptosisremains a matter of debate. We found that TRAIL treatment resulted in robust depolarizationin human melanoma cells with a considerable lag (2-4 h). Moreover, membrane-depolarizingagents, including K+ and ATP-sensitive K+ (KATP) channel inhibitors glibenclamideand U37883A enhanced TRAIL-induced apoptosis. On the contrary, inhibitors of calcium-and voltage-dependent K+ channels and mitochondrial KATP channels had no sucheffects. Melanocytes were insensitive to TRAIL-induced depolarization and apoptosisas well as to the sensitization by membrane-depolarizing agents despite theirsubstantial surface expression of death receptors. TRAIL induced robust activationof X-box-binding protein-1 and caspase-12, both of which were enhanced by theK+ and KATP channel inhibitors, but not by other K+ channel inhibitors. Finally,caspase-12-selective inhibitor completely abolished the amplification of apoptosis.These findings suggest that depolarization promotes endoplasmic reticulum stress-mediateddeath pathway, thereby amplifying TRAIL cytotoxicity. Thus, membrane-depolarizingagents such as KATP channel inhibitors may have therapeutic potential in the treatmentof TRAIL-resistant cancer cells without impairing tumor-selectivity.

Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: Role for ATP-sensitive K+ channels and endoplasmic reticulum stress