Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma

We demonstrated here that hypoxia significantly attenuated sensitivity of Hepatocellular carcinoma cells to sorafenib treatment and reduced its proliferation

Chao Liang; Zhebin Dong; Xianlei Cai; Jie Shen; Yuan Xu; Miaozun Zhang; Hong Li; Weiming Yu; Wei Chen

2020

Scholarcy highlights

  • Hepatocellular carcinoma, the most common type of liver cancer, is still a major medical burden worldwide so far
  • These results indicated that hypoxia attenuated the cytotoxicity of sorafenib to HCC cells in vitro
  • Liu et al reported that B-cell lymphoma-2/adenovirus E1B 19 kDa-interacting protein 3 and B-cell lymphoma-2/adenovirus E1B kDa-interacting protein 3-like protein X, the Hif-1α target genes, were activated by hypoxia and induced mitophagy, a specific form of autophagy, which may involve in sorafenib resistance
  • Inhibition of autophagy induced by hypoxia in sorafenib-treated HCC cells exhibited a similar effort in killing HCC cells compared to those in normoxia
  • These results indicated us autophagy is a relative major mechanism in mediating hypoxiainduced sorafenib resistance, otherwise inhibition of autophagy of sorafenib-treated HCC cells in hypoxia would not achieve the same effect to those in normoxia if existing other major pro-survival pathways hypoxia could activate
  • We found autophagy induced by sorafenib itself was important in mediating sorafenib resistance, inhibition of sorafenib-induced autophagy significantly enhanced cytotoxicity of sorafenib in HCC cells
  • Our founding revealed that hypoxiainduced autophagy is a main mechanism mediating sorafenib resistance in Hepatocellular carcinoma cells and FOXO3a plays a key role in regulating hypoxia-induced autophagy in vitro and in vivo

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