Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The death ligand TRAIL represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limit its applicability. A new approach is presented here for sensitization to TRAIL. It is based on inhibition of the membrane potassium channel KCa3.1 (IK1), which serves fundamental cellular functions related to membrane potential. The selective inhibitor TRAM-34 did not induce apoptosis by itself but synergistically enhanced TRAIL sensitivity and overrode TRAIL resistance in a large panel of melanoma cell lines. Expression of IK1 was also found in mitochondria, and its inhibition resulted in mitochondrial membrane hyperpolarization and an early activation of Bax. The combination of TRAM-34 and TRAIL resulted in massive release of mitochondrial factors, cytochrome c, AIF and SMAC/DIABLO. Bax knockdown and Bcl-2 overexpression abolished apoptosis. Overexpression of XIAP diminished apoptosis by two-fold, and SMAC knockdown almost completely abolished apoptosis. These data uncover the existence of a rheostat in melanoma cells, consisting of inhibitor of apoptosis proteins and SMAC, which regulates TRAIL sensitivity. Thus, a new strategy is described based on mitochondrial membrane channels, which correspond to Bax activation. As both TRAIL and IK1 inhibitors had shown only minor side effects in clinical trials, a clinical application of this combination is conceivable.
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PMID:General Sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC. 2272 88

The death ligand TRAIL (TNF-related apoptosis-inducing ligand) represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limits its applicability and therapeutic use. Recent work has revealed that combinations with survival pathway inhibitors could efficiently sensitize melanoma cells for TRAIL. Here, a particular role was attributed to the activation of Bax, which is regulated by phosphorylation. Thus, TRAIL resistance in melanoma is explained by three major steps, namely high levels of antiapoptotic Bcl-2 proteins, high levels of inhibitor of apoptosis proteins (cIAPs) and suppressed Bax activity. Importantly, Bid was activated in response to TRAIL alone also in resistant cells to antagonize Bcl-2, and Bax was activated in response to pathway inhibitors. However, only in combinations, mitochondrial apoptosis pathways were opened to result in release of Smac/DIABLO, which functions as antagonist of cIAPs. Opening the caspase cascade by Smac then allowed efficient induction of apoptosis. Thus, direct or indirect targeting of Bax represents a suitable strategy to overcome TRAIL resistance in melanoma and may allow the establishment of TRAIL-based therapeutic approaches.
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PMID:Sensitization of melanoma cells for TRAIL-induced apoptosis by activation of mitochondrial pathways via Bax. 2436 24