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Eukaryotic elongation factor-2 kinase (eEF-2K),a negative regulator of protein synthesis,has been shown to play an important role in modulating autophagy and apoptosis in tumor cells under various stresses.In this study,we investigated the regulatory role of eEF-2K in pyroptosis (a new form of programmed necrosis) in doxorubicin-treated human melanoma cells.We found that doxorubicin (0.5-5 μmol/L) induced pyroptosis in melanoma cell lines SK-MEL-5,SK-MEL-28,and A-375 with high expression of DFNA5,but not in human breast cancer cell line MCF-7 with little expression of DFNA5.On the other hand,doxorubicin treatment activated autophagy in the melanoma cells;inhibition of autophagy by transfecting the cells with siRNA targeting Beclin1 or by pretreatment with chloroquine (20 μmol/L) significantly augmented pyroptosis,thus sensitizing the melanoma cells to doxorubicin.We further demonstrated that doxorubicin treatment activated eEF-2K in the melanoma cells,and silencing of eEF-2K blunted autophagic responses,but promoted doxorubicin-induced pyroptotic cell death.Taken together,the above results demonstrate that eEF-2K dictates the cross-talk between pyroptosis and autophagy in doxorubicin-treated human melanoma cells;suppression of eEF-2K results in inhibiting autophagy and augmenting pyroptosis,thus modulating the sensitivity of melanoma cells to doxorubicin,suggesting that targeting eEF-2K may reinforce the antitumor efficacy of doxorubicin,offering a new insight into tumor chemotherapy.