Hsp90 Alpha Mediates Sorafenib Resistance In Human Hepatocellular Carcinoma By Necroptosis Inhibition Under Hypoxia

Simple SummaryHypoxia is one of the characteristics of most solid tumors and induces cell resistant to chemotherapy. In this paper, we established a hypoxia model in both in vitro and in vivo to investigate the mechanisms of Sorafenib resistance in Hepatocellular carcinoma (HCC). Here, we observed that necroptosis could be an important target of Sorafenib in liver cancer and necroptosis blocking might be important in Sorafenib resistance under hypoxia. Mechanistically, our work suggests that HSP90 alpha plays a pivotal role in Sorafenib-induced necroptosis by binding with necrosome. HSP90 alpha could promote MLKL chaperone-mediated autophagy degradation in hypoxia, which subsequently decreased necroptosis. Consequently, the inhibition of necroptosis contributes to Sorafenib resistant. The Sorafenib resistance was reversed by HSP90 alpha inhibitor-Demethoxygeldanamycin (17-AAG) in vivo and in vitro. This study highlights the important role of HSP90 alpha in Sorafenib resistance under hypoxia microenvironment, and provides a potential therapy target for liver cancer.As one of the most common malignancies worldwide, Hepatocellular carcinoma (HCC) has been treated by Sorafenib, which is the first approved target drug by FDA for advanced HCC. However, drug resistance is one of the obstacles to its application. As a typical characteristic of most solid tumors, hypoxia has become a key cause of resistance to chemotherapy and radiotherapy. It is important to elucidate the underlying mechanisms of Sorafenib resistance under hypoxia. In this study, the morphological changes of hepatocellular carcinoma cells were observed by Live Cell Imaging System and Transmission Electron Microscope; Sorafenib was found to induce necroptosis in liver cancer. Under hypoxia, the distribution of necroptosis related proteins was changed, which contributed to Sorafenib resistance. HSP90 alpha binds with the necrosome complex and promotes chaperone-mediated autophagy (CMA) degradation, which leads necroptosis blocking and results in Sorafenib resistance. The patient-derived tumor xenograft (PDX) model has been established to investigate the potential therapeutic strategies to overcome Sorafenib resistance. 17-AAG inhibited HSP90 alpha and presented obvious reversal effects of Sorafenib resistance in vivo and in vitro. All the results emphasized that HSP90 alpha plays a critical role in Sorafenib resistance under hypoxia and 17-AAG combined with Sorafenib is a promising therapy for hepatocellular carcinoma.