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

International Journal of Biological Sciences
Yao-Chen WangHuei Lee

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/...Continue Reading

Citations

Aug 28, 2019·Oncology Letters·Hui-Li WangJia-Hui Yang
Sep 13, 2019·BioMed Research International·Longfei YangLufei Wang
Feb 15, 2021·European Journal of Medicinal Chemistry·Yang LiuLixia Chen
May 6, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Jian XuYing-Wei Li

❮ Previous
Next ❯

Methods Mentioned

BETA
immunoprecipitation
PCR
ChIP
surgical resection

Software Mentioned

SPSS

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

Related Papers

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Lecia V SequistJean-Charles Soria
Lung Cancer : Journal of the International Association for the Study of Lung Cancer
Nico van Zandwijk
Annals of Oncology : Official Journal of the European Society for Medical Oncology
Federico CappuzzoMarileila Varella-Garcia
Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
Seiji YanoMasayuki Noguchi
© 2022 Meta ULC. All rights reserved