Hypoxia-mediated activation of autophagic flux inhibits apoptosis of keratinocytes via blocking tumor necrosis factor-related apoptosis-inducing ligand

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is toxic against transformed tumor cells. Cornification is the terminal differentiation of keratinocytes and a specific form of programmed cell death caused by TRAIL that occurs in keratinocytes. Apoptosis can also be triggered when TRAIL induces expression of keratinocyte differentiation markers. The present study reported that hypoxia inhibits TRAIL-induced apoptosis due to autophagic flux. It is well known that hypoxia activates autophagy in keratinocytes and reduces p62 protein levels. The present study demonstrated that hypoxia inhibited TRAIL-mediated apoptosis and induced autophagic flux in HaCaT cells. In addition, autophagic flux-inactivating reagents, including 3-methyladenine and chloroquine, increased the TRAIL sensitivity of HaCaT cells exposed to hypoxia. In conclusion, these results indicated that inactivating autophagy increased TRAIL sensitivity in hypoxic HaCaT cells. Autophagy inhibitors may be beneficial in therapies using TRAIL against skin cancers.