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

Yao Chen Wang, De Wei Wu, Tzu Chin Wu, Lee Wang, Chih Yi Chen, Huei Lee

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)47-56
Number of pages10
JournalInternational Journal of Biological Sciences
Volume14
Issue number1
DOIs
Publication statusPublished - Jan 11 2018

Fingerprint

src Homology Domains
adenocarcinoma
Phosphoric Monoester Hydrolases
Epidermal Growth Factor Receptor
phosphatase
Protein-Tyrosine Kinases
Tyrosine
tyrosine
inhibitor
phosphotransferases (kinases)
Down-Regulation
lungs
Mitogen-Activated Protein Kinase Kinases
phosphatidylinositol 3-kinase
Phosphatidylinositol 3-Kinases
mitogen-activated protein kinase
cells
Messenger RNA
relapse
dioscin

Keywords

  • Dioscin
  • EGFR
  • Lung adenocarcinoma

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Dioscin overcome TKI resistance in EGFR-mutated lung adenocarcinoma cells via down-regulation of tyrosine phosphatase SHP2 expression. / Wang, Yao Chen; Wu, De Wei; Wu, Tzu Chin; Wang, Lee; Chen, Chih Yi; Lee, Huei.

In: International Journal of Biological Sciences, Vol. 14, No. 1, 11.01.2018, p. 47-56.

Research output: Contribution to journalArticle

Wang, Yao Chen ; Wu, De Wei ; Wu, Tzu Chin ; Wang, Lee ; Chen, Chih Yi ; Lee, Huei. / Dioscin overcome TKI resistance in EGFR-mutated lung adenocarcinoma cells via down-regulation of tyrosine phosphatase SHP2 expression. In: International Journal of Biological Sciences. 2018 ; Vol. 14, No. 1. pp. 47-56.
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