Cx32 mediates norepinephrine‐promoted EGFR‐TKI resistance in a gap junction‐independent manner in non‐small‐cell lung cancer. Issue 12 (31st May 2019)

• Record Type: Journal Article
• Authors: Xie, Jie; Wang, Xiyan; Ge, Hui; Peng, Fuhua; Zheng, Ningze; Wang, Qin; Tao, Liang
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 12(2019:Dec.)
• Page Start: 23146
• Page End: 23159
• Publication Date: 2019-05-31
• Subjects: Afatinib -- Cx32 -- drug resistance -- norepinephrine -- NSCLC; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.28881
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: 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 β2 ‐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. Abstract : Stress hormone norepinephrine accelerates Afatinib resistance by increasing the expression of Cx32 through the PKA/CREB pathway. Cx32 promotes Afatinib resistance in non‐small‐cell lung cancer by upregulating MET and IGF‐1R expression as well as by inhibiting MET and IGF‐1R degradation.