Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Uro-Oncology Institute of Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Pharmacol Res. 2023 Jun;192:106789. doi: 10.1016/j.phrs.2023.106789. Epub 2023 May 4.
Oral multitarget tyrosine kinase inhibitors (TKIs), such as sorafenib, which suppress tumor cell proliferation and tumor angiogenesis, have been approved to treat patients with hepatocellular carcinoma (HCC). Of note, only approximately 30% of patients can benefit from TKIs, and this population usually acquires drug resistance within 6 months. In this study, we intended to explore the mechanism associated with regulating the sensitivity of HCC to TKIs. We revealed that integrin subunit β 5 (ITGB5) is abnormally expressed in HCC and contributes to decreased the sensitivity of HCC to sorafenib. Mechanistically, unbiased mass spectrometry analysis using ITGB5 antibodies revealed that ITGB5 interacts with EPS15 to prevent the degradation of EGFR in HCC cells, which activates AKT-mTOR signaling and the MAPK pathway to reduce the sensitivity of HCC cells to sorafenib. In addition, mass spectrometry analysis showed that CSNK1A1 binds to ITGB5 in HCC cells. Further study indicated that ITGB5 increased the protein level of CSNK1A1 through the EGFR-AKT-mTOR pathway in HCC. Upregulated CSNK1A1 phosphorylates ITGB5 to enhance the interaction between ITGB5 and EPS15 and activate EGFR in HCC cells. Thus, we identified a positive feedback loop between ITGB5-EPS15-EGFR-CSNK1A1 in HCC cells. This finding provides a theoretical basis for the future development of therapeutic strategies to improve the anti-HCC efficacy of sorafenib.
口服多靶点酪氨酸激酶抑制剂（TKI），如索拉非尼，可抑制肿瘤细胞增殖和肿瘤血管生成，已被批准用于治疗肝细胞癌（HCC）患者。值得注意的是，只有约 30%的患者可以从 TKI 中获益，而这部分人群通常在 6 个月内会产生耐药性。在本研究中，我们旨在探索与调节 HCC 对 TKI 敏感性相关的机制。我们发现整合素亚基β5（ITGB5）在 HCC 中异常表达，导致 HCC 对索拉非尼的敏感性降低。从机制上讲，使用 ITGB5 抗体进行的无偏质谱分析表明，ITGB5 与 EPS15 相互作用，以防止 HCC 细胞中 EGFR 的降解，从而激活 AKT-mTOR 信号通路和 MAPK 通路，降低 HCC 细胞对索拉非尼的敏感性。此外，质谱分析表明，CSNK1A1 在 HCC 细胞中与 ITGB5 结合。进一步的研究表明，ITGB5 通过 HCC 中的 EGFR-AKT-mTOR 通路增加 CSNK1A1 的蛋白水平。上调的 CSNK1A1 磷酸化 ITGB5，增强 HCC 细胞中 ITGB5 与 EPS15 之间的相互作用，并激活 EGFR。因此，我们在 HCC 细胞中鉴定了一个 ITGB5-EPS15-EGFR-CSNK1A1 之间的正反馈环。这一发现为未来开发提高索拉非尼抗 HCC 疗效的治疗策略提供了理论基础。
