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

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.

• Authors: Yao-Chen Wang, De-Wei Wu, Tzu-Chin Wu, Lee Wang, Chih-Yi Chen, Huei Lee
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 14 Issue 1 Pg. 47-56 ( 2018) ISSN: 1449-2288 [Electronic] Australia
• PMID: 29483824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Enzyme Inhibitors
• GAB1 protein, human
• Reactive Oxygen Species
• dioscin
• ErbB Receptors
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Diosgenin

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Adenocarcinoma of Lung (drug therapy, genetics)
• Apoptosis (genetics, physiology)
• Blotting, Western
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Diosgenin (analogs & derivatives, pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• ErbB Receptors (genetics)
• Gene Expression Regulation, Enzymologic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mutation (genetics)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)