Ixazomib promotes CHOP-dependent DR5 induction and apoptosis in colorectal cancer cells

作者：Yue, Dan^*; Sun, Xun

来源：Cancer Biology and Therapy, 2019, 20(3): 284-294.

DOI：10.1080/15384047.2018.1529095

• Ixazomib
• TRAIL
• death receptor 5
• extrinsic apoptotic pathway
• CHOP

Background: Ixazomib (Ninlaro), a novel proteasome inhibitor, has been developed for the treatment of many cancers and has demonstrated anti-tumor efficacy against various malignancies. However, the mechanism of the anti-tumor effect of ixazomib in colorectal cancer (CRC) cells remains unclear. Methods: MTS and flow cytometry were performed to determine the effect of ixazomib on CRC cells. Western blotting and real-time RT-PCR were performed to detect ixazomib-induced DR5 upregulation. ChIP was performed to detect CHOP binding to DR5 promoter. Finally, xenograft experiments were carried out to measure the antitumor effect of ixazomib in vivo. Results: In this study, we revealed the mechanism by which ixazomib inhibits the growth of CRC cells. Our findings indicated that ixazomib treatment induces CHOP-dependent DR5 induction, irrespective of p53 status. Furthermore, DR5 is necessary for ixazomib-mediated apoptosis. Ixazomib also synergized with TRAIL to induce marked apoptosis via DR5 in CRC cells. Conclusions: Our findings further suggested that ixazomib sensitizes TRAIL/death receptor signaling pathway-targeted CRC and suggested that DR5 induction could be a valuable indicator of ixazomib sensitivity.

• 出版日期2019-3-4
• 单位中国医科大学