Cytoplasmic P120ctn Promotes Gefitinib Resistance in Lung Cancer Cells by Activating PAK1 and ERK Pathway.

Abstract

Our previous studies indicated that cytoplasmic p120ctn mediated epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) resistance in lung cancer. In the present study, we aim to further explore the underlying molecular mechanisms. Immunohistochemistry detected PAK1, Cdc42, and Rac1 expression in lung cancer with cytoplasmic p120ctn. Immunoblotting, protein activity analysis, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide evaluated p120ctn location, PAK1, Cdc42/Rac1, and extracellular signal-regulated kinase (ERK) activity in response to TKI treatment in HCC827 and PC9 cell lines, as well as the cell sensitivity to Gefitinib. Most non-small cell lung cancer patients with cytoplasmic p120ctn showed enhanced PAK1 and Cdc42/Rac1. When Gefitinib resistance was induced, cytoplasmic p120ctn is accompanied with increasing PAK1 and Cdc42/Rac1. Cytoplasmic p120ctn activated ERK via PAK1, while PAK1 downregulation attenuated ERK activation by cytoplasmic p120ctn. After Cdc42/Rac1 inhibition, cytoplasmic p120ctn could not activate PAK1. Cytoplasmic p120ctn activates PAK1 via Cdc42/Rac1 activation, constitutively activates ERK in the EGFR downstream signaling, and promotes EGFR-TKI resistance in lung cancer cells. The current study will aid to screen the subpopulation patients who would benefit from therapy with first-generation EGFR-TKIs.

• Authors: Wei-Wei Liu, Jing Hu, Rui Wang, Qiang Han, Yang Liu, Si Wang
• Journal: Applied immunohistochemistry & molecular morphology : AIMM (Appl Immunohistochem Mol Morphol) 2021 Nov-Dec 01 Vol. 29 Issue 10 Pg. 750-758 ISSN: 1533-4058 [Electronic] United States
• PMID: 34412070 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• Catenins
• Neoplasm Proteins
• PAK1 protein, human
• p21-Activated Kinases
• Gefitinib
• Delta Catenin
• CTNND1 protein, human

Topics

• Catenins (metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Enzyme Activation (drug effects)
• Female
• Gefitinib (pharmacology)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• MAP Kinase Signaling System (drug effects)
• Male
• Neoplasm Proteins (metabolism)
• p21-Activated Kinases (metabolism)
• Delta Catenin