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.