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

Abstract

Sorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.

Development and validation of prognostic model based on the analysis of autophagy-related genes in colon cancer

“…Conversely, autophagy can trigger cell death under certain conditions, such as over-regulation of autophagy or long-term exposure to autophagy [ 8 ]. Autophagy has played an important intermediary role in terms of resistance to radiation, chemotherapy, and targeted agents [ 9 , 10 ].…”

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

“…This study suggested that a homeostasis of autophagy is maintained by FOXO3a and is crucial to cancer cell survival. In contradiction to what is described above, FOXO3a was reported to play a promoting role in both hypoxia-induced and sorafenib-induced autophagy and sorafenib resistance in hepatocellular carcinoma, while the knockout of FOXO3a significantly inhibited autophagy and restored sorafenib sensitivity [ 104 ] .…”

“…Forkhead box (FOX) O3a, a transcription factor suppressing protective autophagy particularly in CSCs, was identified to form a negative feedback loop in which its turnover was controlled by autophagy. Upon autophagy inhibition, FOXO3a protein increased and accumulated in the nucleus, and transcriptionally activated the pro-apoptotic gene, p53 upregulated modulator of apoptosis, leading to p53-independent apoptosis and consequently sensitizing colorectal cancer (CRC) cells to chemotherapy drugs such as doxorubicin and etoposide [103] . This study suggested that a homeostasis of autophagy is maintained by FOXO3a and is crucial to cancer cell survival.…”

Elucidating the Molecular Basis of Sorafenib Resistance in HCC: Current Findings and Future Directions

“…FOXO3a transcriptionally activates Beclin-1 enhancing autophagosome enucleation and increasing the overall autophagic flux and its knockdown in vivo increased sorafenib efficacy. 93 These findings raise controversial debates on the FOXO3 role in autophagy control under hypoxic conditions underlining once again the multifaceted aspects and effects of autophagy in cancer progression and sorafenib response. In summary, here we show the induction of hypoxia following sorafenib treatment as a double-edged sword that rather than prompting its antiangiogenic effect is especially implicated in long-term acquired resistance and tumor escape giving cancer cells a pro-survival advantage in low oxygen conditions ( Figure 3 ).…”