α‑hederin overcomes hypoxia‑mediated drug resistance in colorectal cancer by inhibiting the AKT/Bcl2 pathway
Jinbao Chen, Jian Xu, Jiahua Yang, Yueping Zhan, Sen Li, Linlin Jia, Wentao Wu, Xianke Si, Die Zhang, Kun Yu, Peihao Yin, Yijun Cao, Wanli Deng, Ke Xu, Wei Li
Abstract
Currently, chemoresistance is a major challenge that directly affects the prognosis of patients with colorectal cancer (CRC). In addition, hypoxia is associated with poor prognosis and therapeutic resistance in patients with cancer. Accumulating evidence has shown that α‑hederin has significant antitumour effects and that α‑hederin can inhibit hypoxia‑mediated drug resistance in CRC; however, the underlying mechanism remains unclear. In the present study, viability and proliferation assays were used to evaluate the effect of α‑hederin on the drug resistance of CRC cells under hypoxia. Sequencing analysis and apoptosis assays were used to determine the effect of α‑hederin on apoptosis under hypoxia. Western blot analysis and reverse transcription‑quantitative PCR were used to measure apoptosis‑related protein and mRNA expression levels. Furthermore, different mouse models were established to study the effect of α‑hederin on hypoxia‑mediated CRC drug resistance <em>in vivo</em>. In the present study, the high expression of Bcl2 in hypoxic CRC cells was revealed to be a key factor in their drug resistance, whereas α‑hederin inhibited the expression of Bcl2 by reducing AKT phosphorylation <em>in vitro</em> and <em>in vivo</em>, and promoted the apoptosis of CRC cells under hypoxia. By contrast, overexpression of AKT reversed the effect of α‑hederin on CRC cell apoptosis under hypoxia. Taken together, these results suggested that α‑hederin may overcome hypoxia‑mediated drug resistance in CRC by inhibiting the AKT/Bcl2 pathway. In the future, α‑hederin may be used as a novel adjuvant for reversing drug resistance in CRC.