Effect of erythropoietin production induced by hypoxia on autophagy in HepG2 cells

Abstract The induction of hypoxia inducible factor (HIF) and autophagy are important cellular responses to hypoxia. The production of erythropoietin (EPO) regulated by HIF is increased by hypoxia and participates in cell protection in various organs and tissues. Signal Transducers and Activator of Transcription 3 (STAT3) is a regulatory factor that is common to autophagy induction and EPO-EPO receptor signaling. In this study, we analyzed the promotion of EPO production and autophagy, and the participation of STAT3, in HepG2 cells under hypoxia. Treatment with EPO siRNA (si-EPO) significantly increased autophagy induction by hypoxia, while treatment with recombinant EPO inhibited the effect of si-EPO. NSC74859, an inhibitor of the phosphorylation of STAT3, increased autophagy induction to the same extent as si-EPO treatment. Even when 3-Methyladenine, an inhibitor of autophagy, was added, the increase of EPO mRNA expression due to hypoxia was not affected. Hypoxia-induced EPO restrained autophagy induction through the EPO receptor and phosphorylation of STAT3. Because cell viability with treatment of si-EPO under hypoxia did not increase over the control, our results suggested that EPO produced by hypoxia prevented excess autophagy induction.