Distinct characteristics of dasatinib-induced pyroptosis in gasdermin E-expressing human lung cancer A549 cells and neuroblastoma SH-SY5Y cells.

Abstract

Dasatinib, a multikinase inhibitor, is used in the treatment of chronic myeloid leukemia and was developed to overcome imatinib resistance. Its mechanism of action involves the induction of apoptosis, autophagy and necroptosis. However, it remains unclear whether dasatinib can induce pyroptosis. In the present study, gasdermin E (GSDME)-expressing SH-SY5Y and A549 cells were chosen for investigation. Typical pyroptotic features, such as cleavage of GSDME protein, leakage of lactate dehydrogenase and large bubbled morphology, were observed in both cell lines after exposure to dasatinib. The generation of GSDME fragments was inhibited by specific caspase-3 inhibitor zDEVD in SH-SY5Y cells and pan-caspase inhibitor zVAD in A549 cells. Moreover, distinct characteristics of pyroptosis were observed in A549 cells, which occurred only with a high percentage of Annexin V/propidium iodide double-stained cells and low level of GSDME protein cleavage. The sensitivity of A549 cells to dasatinib is significantly reduced by increasing cell numbers. The elevation of GSDMD and GSDME protein levels was induced by low concentrations of dasatinib, which was not influenced by the reduction of p53 protein with RNA interference. In conclusion, to the best of our knowledge, this is the first study to report that dasatinib can induce pyroptosis in tumor cells and increase the protein levels of GSDMD and GSDME in a p53-independent manner.