Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
Department of Hepatobiliary and Pancreas Surgery, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, 524000, Guangdong, China.
Oncogene. 2021 Jan;40(3):492-507. doi: 10.1038/s41388-020-01545-z. Epub 2020 Nov 12.
Sorafenib resistance has become the main obstacle in the effective treatment of advanced hepatocellular carcinoma (HCC) patients. Activation of nuclear factor kappa B (NF-κB) is a newly identified mechanism that contributes to desensitized sorafenib. Cytochrome P450 1A2 (CYP1A2) functions as a tumor suppressor in HCC and its expression is negatively associated with NF-κB in the liver. This study aimed to study whether CYP1A2 could overcome sorafenib resistance. To investigate whether CYP1A2 and NF-κB p65 played roles in sorafenib desensitization, we established sorafenib-resistant (SR) HCC cells. SR cells decreased the expression of CYP1A2 along with the upregulation of NF-κB p65. CYP1A2 overexpression attenuated SR cell proliferation, increased sorafenib sensitivity, and inhibited the NF-κB pathway, whereas CYP1A2 silence showed opposite effects. Sorafenib, in combination with omeprazole, a CYP1A2 inducer, significantly hindered the growth and invasion of SR cells in vitro as well as decreased the tumor growth in vivo. The combination treatment markedly increased CYP1A2 expression and inhibited the sorafenib-induced NF-κB signaling. In addition, the overexpression of NF-κB p65 stimulated the SR cell growth and desensitized sorafenib in SR cells, where CYP1A2 overexpression reversed the phenomenon. Lastly, the majority of HCC tissue samples displayed decreased CYP1A2 but increased NF-κB p65 protein expression. Collectively, CYP1A2 can sensitize SR cells to sorafenib via inhibiting NF-κB p65 axis. Omeprazole in combination with sorafenib exerts a synergistic effect in alleviating acquired sorafenib resistance.
索拉非尼耐药已成为晚期肝细胞癌 (HCC) 患者有效治疗的主要障碍。核因子-κB (NF-κB) 的激活是一种新发现的机制，有助于索拉非尼脱敏。细胞色素 P450 1A2 (CYP1A2) 在 HCC 中作为一种肿瘤抑制因子发挥作用，其表达与肝脏中的 NF-κB 呈负相关。本研究旨在研究 CYP1A2 是否可以克服索拉非尼耐药。为了研究 CYP1A2 和 NF-κB p65 是否在索拉非尼脱敏中发挥作用，我们建立了索拉非尼耐药 (SR) HCC 细胞。SR 细胞降低 CYP1A2 的表达，同时上调 NF-κB p65。CYP1A2 的过表达减弱了 SR 细胞的增殖，增加了索拉非尼的敏感性，并抑制了 NF-κB 通路，而 CYP1A2 的沉默则表现出相反的效果。索拉非尼与 CYP1A2 诱导剂奥美拉唑联合使用，显著抑制了 SR 细胞在体外的生长和侵袭，并降低了体内肿瘤的生长。联合治疗显著增加了 CYP1A2 的表达并抑制了索拉非尼诱导的 NF-κB 信号通路。此外，NF-κB p65 的过表达刺激了 SR 细胞的生长并使 SR 细胞对索拉非尼脱敏，而过表达 CYP1A2 则逆转了这一现象。最后，大多数 HCC 组织样本显示 CYP1A2 表达降低而 NF-κB p65 蛋白表达增加。综上所述，CYP1A2 可以通过抑制 NF-κB p65 轴使 SR 细胞对索拉非尼敏感。奥美拉唑与索拉非尼联合使用在缓解获得性索拉非尼耐药方面具有协同作用。
