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Induction of autophagy by cisplatin‐resistant esophageal cancer cells promotes survival and recovery

Esophageal squamous cell carcinoma (ESCC) is a highly malignant disease with a poor prognosis. Cisplatin‐chemotherapy is widely used for the treatment of this malignancy. However, the clinical efficacy of this drug is limited due to intrinsic and acquired resistance to it. Autophagy is an evolutionarily conserved lysosomal degradation pathway. Induction of autophgay has emerged as a drug resistance mechanism that promotes cancer cell survival. In this study, we investigated cellular response after treatment with cisplatin in ESCC cells. Cisplatin‐resistanct cell lines exhibited reduced apoptosis and senescence compared with cisplatin‐sensitive counterparts. Moreover, cisplatin treatment induced autophagy in resistant cells but not in their sensitive counterparts. The induction of autophagy was evidenced by the formation of LC3+ autophagosomes and decreased p62 protein level and was accompanied by the suppression of mammalian target of rapamycin complex 1 activity. Inhibition of autophagy induction by knockdown of ATG5 or ATG7 significantly reduced the clonogenic survival of cisplatin‐treated resistant cells. Disruption of lysosomal activity with chloroquine improved chemotherapeutic effect of cisplatin in resistant cancer cells both in vitro and in vivo. In addition, cisplatin increased phosphorylation of ERK, p38 and JNK, but only inhibition of ERK activation significantly attenuated the recovery of cisplatin‐treated cells. Moreover, MEK inhibitor attenuated cisplatin‐induced cellular apoptosis and senescence. To conclude, this study demonstrates that an autophagic response to cisplatin is a survival mechanism that promotes chemo‐resistance and recovery. This finding suggests that the combination of autophagy inhibitors with cisplatin may have significant potential clinical application in the circumvention of cisplatin‐resistant ESCC.