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Int J Biol Sci 2018; 14(1):47-56. doi:10.7150/ijbs.22209

Research Paper

Dioscin overcome TKI resistance in EGFR-mutated lung adenocarcinoma cells via down-regulation of tyrosine phosphatase SHP2 expression

Yao-Chen Wang1,2, De-Wei Wu5, Tzu-Chin Wu1,2, Lee Wang3, Chih-Yi Chen2,4, Huei Lee5✉

1. Department of Internal Medicine, Chung Shan Medical University and Hospital, Taichung, Taiwan.
2. School of Medicine, Chung Shan Medical University and Hospital, Taichung, Taiwan.
3. Department of Public Health, Chung Shan Medical University, Taichung, Taiwan.
4. Department of Surgery, Chung Shan Medical University and Hospital, Taichung, Taiwan.
5. Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.

Abstract

Resistance to tyrosine kinase inhibitors (TKIs) results in tumor relapse and poor prognosis in patients with lung adenocarcinoma. TKI resistance caused by epidermal growth factor receptor (EGFR) mutations at T790M and c-Met amplification occurs through persistent activation of the MEK/ERK and PI3K/AKT signaling pathways. We therefore expected that dual inhibitors of both signaling pathways could overcome TKI resistance in lung adenocarcinoma. Here, dioscin was selected from a product library of Chinese naturally occurring compounds and overcame TKI resistance in EGFR-mutated lung adenocarcinoma cells. Mechanistically, dioscin may down-regulate the expression of SH2 domain-containing phosphatase-2 (SHP2) at the transcription level by increasing p53 binding to the SHP2 promoter due to reactive oxygen species (ROS). Simultaneous inhibition of MEK/ERK and PI3K/AKT activation via decreased SHP2 expression and its interaction with GAB1 may be responsible for dioscin-mediated TKI sensitivity. A higher unfavorable response to TKI therapy occurred more commonly in patients with high SHP2 mRNA expression than in patients with low SHP2 mRNA expression. Therefore, we suggest that dioscin may act as a dual inhibitor of the MEK/ERK and PI3K/AKT signaling pathways to overcome TKI resistance via dysregulation of SHP2 expression in lung adenocarcinoma.

Keywords: Dioscin, EGFR, lung adenocarcinoma

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How to cite this article:
Wang YC, Wu DW, Wu TC, Wang L, Chen CY, Lee H. Dioscin overcome TKI resistance in EGFR-mutated lung adenocarcinoma cells via down-regulation of tyrosine phosphatase SHP2 expression. Int J Biol Sci 2018; 14(1):47-56. doi:10.7150/ijbs.22209. Available from http://www.ijbs.com/v14p0047.htm