Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Tumor Research Institute, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang, China.
J Cell Physiol. 2019 Dec;234(12):23146-23159. doi: 10.1002/jcp.28881. Epub 2019 May 31.
The second-generation EGFR-TKI Afatinib is an irreversible ErbB family blocker used to treat patients with non-small-cell lung cancer (NSCLC). Unfortunately, resistance to this drug develops over time, and patients are always under great psychological pressure. A previous study showed that chronic stress hormones participate in EGFR-TKI resistance via β -AR signaling via an IL-6 dependent mechanism. Our study further explores a novel potential underlying mechanism. In the present study, we show that the stress hormone norepinephrine (NE) promotes Afatinib resistance by upregulating Cx32 expression. Furthermore, we, for the first time, find that Cx32 is a target gene for transcription factor CREB and NE enhances Cx32 mRNA expression by activation of CREB. We also demonstrate that Cx32 promotes Afatinib resistance by decreasing the degradation of EGFR-TKI resistance-associated proteins (MET, IGF-1R) and by increasing their transcription levels. Together, these results reveal that the stress hormone NE accelerates Afatinib resistance by increasing the expression of Cx32, which augments MET and IGF-1R levels in cancer cells and provides a promising therapeutic strategy against EGFR-TKI Afatinib resistance in NSCLC.
第二代 EGFR-TKI 阿法替尼是一种不可逆的 ErbB 家族阻滞剂，用于治疗非小细胞肺癌（NSCLC）患者。不幸的是，随着时间的推移，这种药物会产生耐药性，患者始终承受着巨大的心理压力。先前的一项研究表明，慢性应激激素通过β-AR 信号通过 IL-6 依赖性机制参与 EGFR-TKI 耐药。我们的研究进一步探讨了一种新的潜在机制。在本研究中，我们表明应激激素去甲肾上腺素（NE）通过上调 Cx32 表达促进阿法替尼耐药。此外，我们首次发现 Cx32 是转录因子 CREB 的靶基因，NE 通过激活 CREB 增强 Cx32 mRNA 表达。我们还证明 Cx32 通过降低 EGFR-TKI 耐药相关蛋白（MET、IGF-1R）的降解并增加其转录水平来促进阿法替尼耐药。总之，这些结果表明，应激激素 NE 通过增加 Cx32 的表达加速阿法替尼耐药，从而增加癌细胞中 MET 和 IGF-1R 的水平，并为 NSCLC 中针对 EGFR-TKI 阿法替尼耐药的治疗策略提供了有希望的选择。
