IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways

Peiqi Hao; Ying Huang; Jun Peng; Jiaojiao Yu; Xiaoxi Guo; Fan Bao; Ziqin Dian; Su An; Tian-Rui Xu

doi:10.1016/j.yexcr.2021.112615

IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways

Exp Cell Res. 2021 Jun 15;403(2):112615. doi: 10.1016/j.yexcr.2021.112615. Epub 2021 Apr 21.

Authors

Peiqi Hao¹, Ying Huang², Jun Peng³, Jiaojiao Yu¹, Xiaoxi Guo¹, Fan Bao⁴, Ziqin Dian³, Su An⁵, Tian-Rui Xu⁶

Affiliations

¹ Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China.
² Simcere Pharmaceutical Co., Ltd, Nanjing, 210018, China; The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, 210018, China.
³ The First People's Hospital of Yunnan Province, Kunming, 650032, China.
⁴ Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China; The First People's Hospital of Yunnan Province, Kunming, 650032, China.
⁵ Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China. Electronic address: aslxj@mail.ustc.edu.cn.
⁶ Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China. Electronic address: tianruixu@kust.edu.cn.

PMID: 33894221
DOI: 10.1016/j.yexcr.2021.112615

Abstract

IRS4 is a member of the insulin receptor substrate (IRS) protein family. It acts as a cytoplasmic adaptor protein, integrating and transmitting signals from receptor protein tyrosine kinases to the intracellular environment. IRS4 can induce mammary tumorigenesis and is usually overexpressed in non-small cell lung cancer (NSCLC). However, little is known about the role of IRS4 in the development and progression of lung cancer. In this study, we show that IRS4 knockout suppresses the proliferation, colony formation, migration, and invasion of A549 lung cancer cells, as well as tumor growth in a nude mouse xenograft model. In contrast, stable expression of IRS4 showed the opposite effects. As expected, IRS4 was found to activate the PI3K/Akt and Ras-MAPK pathways, and we also showed that IRS4 depletion significantly enhanced the sensitivity of EGFR tyrosine kinase inhibitor (EGFR-TKI)-resistant cells to gefitinib. Taken together, these results show that IRS4 promotes NSCLC progression and may represent a potential therapeutic target for EGFR-TKI-resistant NSCLC.

Keywords: EGFR-TKI resistance; IRS4; NSCLC; PI3K/Akt; Ras-MAPK.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / therapeutic use*
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / genetics
ErbB Receptors / genetics
ErbB Receptors / metabolism
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Gefitinib / therapeutic use*
Gene Expression Regulation, Neoplastic
Humans
Insulin Receptor Substrate Proteins / antagonists & inhibitors
Insulin Receptor Substrate Proteins / genetics*
Insulin Receptor Substrate Proteins / metabolism
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Male
Mice
Mice, Nude
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
IRS4 protein, human
Insulin Receptor Substrate Proteins
RNA, Small Interfering
EGFR protein, human
ErbB Receptors
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases
Gefitinib