The remodeling of Ca2+ signaling is a common finding in cancer pathophysiology serving the purpose of facilitating proliferation, migration, or survival of cancer cells subjected to stressful conditions.,One particular facet of these adaptive changes is the alteration of Ca2+ fluxes through the plasma membrane, as described in several studies.,In this review, we summarize the current knowledge about the expression of different Ca2+ channels in the plasma membrane of melanoma cells and its impact on oncogenic Ca2+ signaling.,In the last few years, new molecular components of Ca2+ influx pathways have been identified in melanoma cells.,In addition, new links between Ca2+ homeostasis and specific cell processes important in melanoma tumor progression have been unveiled.,Thus, not only do Ca2+ channels appear to have a potential as prognostic markers, but their pharmacological blockade or gene silencing is hinted as interesting therapeutic approaches.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is promising for cancer treatment owing to its selective cytotoxicity against malignant cells.,However, some cancer cell types, including malignant melanoma cells, are resistant to TRAIL-induced apoptosis.,Therefore, drugs that can amplify TRAIL cytotoxicity are urgently required.,Depolarization of the plasma membrane potential is associated with apoptosis induced by a variety of death-inducing agents but its role in apoptosis remains a matter of debate.,We found that TRAIL treatment resulted in robust depolarization in human melanoma cells with a considerable lag (2-4 h).,Moreover, membrane-depolarizing agents, including K+ and ATP-sensitive K+ (KATP) channel inhibitors glibenclamide and U37883A enhanced TRAIL-induced apoptosis.,On the contrary, inhibitors of calcium- and voltage-dependent K+ channels and mitochondrial KATP channels had no such effects.,Melanocytes were insensitive to TRAIL-induced depolarization and apoptosis as well as to the sensitization by membrane-depolarizing agents despite their substantial surface expression of death receptors.,TRAIL induced robust activation of X-box-binding protein-1 and caspase-12, both of which were enhanced by the K+ 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-mediated death pathway, thereby amplifying TRAIL cytotoxicity.,Thus, membrane-depolarizing agents such as KATP channel inhibitors may have therapeutic potential in the treatment of TRAIL-resistant cancer cells without impairing tumor-selectivity.