Targeting hypoxia-inducible factor-2α enhances sorafenib antitumor activity via β-catenin/C-Myc-dependent pathways in hepatocellular carcinoma

Abstract

Abstract. Sorafenib is a type of multikinase inhibitor that exhibits antiangiogenic and antiproliferative effects; in addition, sorafenib is a unique first-line drug recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, the effectiveness of HCC treatment remains poor due to acquired drug resistance. It has been suggested that hypoxia, induced as a results of the antiangiogenic effects of sustained sorafenib treatment, may be an important factor in sorafenib resistance. The transcription factor hypoxia-inducible factor (HIF)-2α has been reported to be associated with cell proliferation under hypoxic conditions; therefore, it was hypothesized that hypoxia may enhance tumor cell proliferation via this mechanism. The present study aimed to evaluate whether the knock-down of HIF-2α was able to enhance the therapeutic efficacy of sorafenib in order to effectively treat HCC. The results demonstrated that hypoxia protected HCC cells against sorafenib; however, short hairpin RNA-HIF-2α transfection in combination with sorafenib treatment exhibited a significantly synergistic effect against HCC cell proliferation. In addition, HCC cells acquired increased β-catenin/C-Myc expression, which enhanced proliferation under hypoxic conditions; however, targeted knock-down of HIF-2α or C-Myc markedly decreased cell proliferation in HCC cells. In conclusion, the results of the present study indicated that the targeted knock-down of HIF-2α in combination with sorafenib may be a promising strategy for the treatment of HCC.

c-Myc promotes tumor proliferation and anti-apoptosis by repressing p21 in rhabdomyosarcomas

“…v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) plays an essential role in cell development as a multifunctional effector of cell cycle progression, metabolism, proliferation, apoptosis, cellular transformation and tumorigenesis (11). A recent study indicated that c-Myc enhances expression of glutamine synthetase (GS), which is responsible for the synthesis of glutamine (Gln) from glutamate (Glu) and ammonia (12).…”

Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells

“…Interestingly, HIF-2α levels were upregulated in both resistant lines against the parental line in the absence and presence of sorafenib, finding also a significant higher HIF-2α translocation to the nucleus. Previous investigations in HCC in vitro models showed that HIF-2α overexpression promotes sorafenib resistance [21], whilst HIF-2α downregulation enhances the antitumor actions of sorafenib [35]. Therefore, the increase in the expression and nuclear translocation of HIF factors in resistant cells seems to be firmly involved in the acquisition of sorafenib resistance and associated with its more aggressive growth.…”

The prognostic role of lactate dehydrogenase serum levels in patients with hepatocellular carcinoma who are treated with sorafenib: the influence of liver fibrosis

“…Recently, using mouse models of primary liver tumors, Bogaerts et al showed that hypoxia in advanced stages resulted in increased expression of liver progenitor cell characteristics that indicate a poor outcome (23). Liu et al demonstrated that the targeted knock-down of hypoxia-inducible factor-2α, which is associated with cell proliferation under hypoxic conditions, in combination with sorafenib, markedly decreased proliferation in HCC cells (24). This supports the possibility that background hypoxia caused by liver fibrosis has detrimental effects on patients treated with sorafenib.…”