Yao Zhicheng, Chen Ang, Li Xin, Zhu Zhiyong, Jiang Xin
Department of Neurology, The People's Hospital of Liaoning ProvinceShenyang, China.
Department of Urinary Surgery, The People's Hospital of Liaoning ProvinceShenyang, China.
Am J Transl Res. 2017 Nov 15;9(11):4945-4953. eCollection 2017.
Heat shock protein 90 (Hsp90), a molecular chaperone, is involved in a variety of physiological and pathological processes. Targeting Hsp90 by small molecules has been developed as an attractive strategy of anticancer therapy. In this study, we investigated the mechanism of Hsp90 inhibitor suppresses CRC growth and potentiates effects of other chemotherapeutic drugs. We found that Hsp90 inhibitor induces chop-dependent DR5 upregulation regardless of p53 status. Furthermore, DR5 is required for Hsp90 inhibitor-induced apoptosis. Hsp90 inhibitor also synergized with TRAIL to induce marked apoptosis via DR5 in CRC. Overall, our results illustrate DR5 play a key role in mediating the anticancer effects of Hsp90 inhibitor in CRC and suggest that DR5 expression can be used as an indicator of Hsp90 inhibitor sensitivity, which has important implications for it clinical applications.
热休克蛋白90（Hsp90）作为一种分子伴侣，参与多种生理和病理过程。通过小分子靶向Hsp90已被开发为一种有吸引力的抗癌治疗策略。在本研究中，我们探究了Hsp90抑制剂抑制结直肠癌（CRC）生长并增强其他化疗药物疗效的机制。我们发现，无论p53状态如何，Hsp90抑制剂均可诱导依赖于CHOP的DR5上调。此外，DR5是Hsp90抑制剂诱导凋亡所必需的。Hsp90抑制剂还与TRAIL协同作用，通过DR5在CRC中诱导显著凋亡。总体而言，我们的结果表明DR5在介导Hsp90抑制剂对CRC的抗癌作用中起关键作用，并提示DR5表达可作为Hsp90抑制剂敏感性的指标，这对其临床应用具有重要意义。
