PLCγ1‑dependent invasion and migration of cells expressing NSCLC‑associated EGFR mutants
| Autor: | Maitreyi S. Rajala, Ann M. Joseph, Arpana Kamath, Sonam Mittal |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Phosphodiesterase Inhibitors Biology Afatinib Cell Line 03 medical and health sciences 0302 clinical medicine Gefitinib Cell Movement Carcinoma Non-Small-Cell Lung medicine Humans Neoplasm Invasiveness Osimertinib Epidermal growth factor receptor Estrenes Kinase activity Protein Kinase Inhibitors Protein kinase B Cell Proliferation Phospholipase C gamma Cell cycle Pyrrolidinones Recombinant Proteins ErbB Receptors 030104 developmental biology Oncology 030220 oncology & carcinogenesis Mutation Cancer research biology.protein Signal transduction Tyrosine kinase Signal Transduction medicine.drug |
| Zdroj: | International Journal of Oncology. |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2020.5112 |
| Popis: | The increased tyrosine kinase activity of nonsmall cell lung cancer (NSCLC)associated epidermal growth factor receptor (EGFR) mutants results in deregulated pathways that contribute to malignant cell survival, tumor progression and metastasis. Previous studies investigating lung cancerassociated EGFR have focused on the prognostic implications of receptor kinase mutations in patients with NSCLC; however, the role of EGFR mutations in tumor cell invasion and migration remains undetermined. The present study was designed to investigate the role of NSCLCassociated mutant EGFRdriven signaling pathways in cell proliferation and invasion. Nonendogenous EGFRexpressing 293 cells stably expressing EGFR mutants that are sensitive or resistant to Food and Drug Administration (FDA)approved EGFRtargeted tyrosine kinase inhibitors (TKIs) were used in the present study. The experiments demonstrated an increased phosphorylation of phospholipase (PLC)I³1, cCbl, signal transducer and activator of transcription (Stat), extracellular regulated kinase (Erk)1/2, Akt, Shc and Gab1 proteins in cells expressing a mutant form, rather than the wildtype receptor. As PLCI³1 is a known regulator of metastatic development, mutant receptormediated PLCI³1 activation was further evaluated. To examine the effects of EGFR and PLCI³1 phosphorylation, the metastatic potential of cells expressing mutants was investigated using wound healing, Transwell cell migration and invasion assays. The inhibition of receptor phosphorylation with the 1st, 2nd and 3rd generation TKIs, gefitinib, afatinib, osimertinib, respectively, reduced PLCI³1 phosphorylation, and reduced the invasive and migratory potential of 293 cells, confirming PLCI³1 as one of the probable downstream effectors of mutant EGFR signaling. However, the PLC inhibitor, U73122, inhibited cell migration and invasion without affecting EGFR signaling and PLCI³1 phosphorylation. Notably, U73122 reduced Akt and Erk1/2 phosphorylation within 25 min of its application; however, 100% cell viability was recorded even after 48 h. Upon further investigation, proliferative signaling pathways remained active at 48 h, in accordance with cell viability. Therefore, the present study concludes that mutant receptormediated PLCI³1 activation may play a significant role in the migration and invasion of NSCLC tumors; however, its regulatory role in tumor cell proliferation warrants further investigation and validation in lung tumor cell lines harboring EGFR mutations. |
| Databáze: | OpenAIRE |
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