p190A RhoGAP is involved in EGFR pathways and promotes proliferation, invasion and migration in lung adenocarcinoma cells

• Published in: International journal of oncology Vol. 43; no. 5; pp. 1569 - 1577
• Main Authors: Notsuda, Hirotsugu, Sakurada, Akira, Endo, Chiaki, Okada, Yoshinori, Horii, Akira, Shima, Hiroshi, Kondo, Takashi
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications UK Ltd 01.11.2013
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Aged; Apoptosis; Blotting, Western; Cell Adhesion; Cell adhesion & migration; Cell Cycle; Cell growth; Cell Movement; Cell Proliferation; Female; Gene amplification; Gene expression; Guanine Nucleotide Exchange Factors - antagonists & inhibitors; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Histology; Humans; Immunoenzyme Techniques; Immunoglobulins; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medical prognosis; Metastasis; Mutation; Neoplasm Invasiveness; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Phosphorylation; Prognosis; Proteins; Real-Time Polymerase Chain Reaction; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - genetics; Repressor Proteins - metabolism; Response rates; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Studies; Survival Rate; Tumor Cells, Cultured; Tumors; United States > US; Japan
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2013.2096

Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs) is an emerging issue in lung cancer treatment. We report evidence that a GTPase-activating protein, p190-A RhoGAP (p190), is a potential molecular target for the treatment of lung adenocarcinoma. We documented inhibition of phosphorylation of p190 by EGFR-TKI treatment in lung adenocarcinoma cell lines. Small interfering RNA-mediated knockdown of p190 leads lung adenocarcinoma cells to growth suppression and to inhibition of invasion/migration through inducing cell cycle arrest but not apoptosis. These findings were observed not only in EGFR-TKI-sensitive cells but also in EGFR-TKI-resistant cells; even in cell lines harboring K-ras mutations. The mechanism of this inhibitory effect on growth and invasion/migration was Ras inactivation through disrupting the p190-A RhoGAP/p120RasGAP complex. In addition, a high level of p190 mRNA expression was observed in majority of surgically obtained tissue from lung adenocarcinoma patients. Overexpression of p190 mRNA associated with poor disease-free survival. The results suggest that overexpression of p190 mRNA may be involved in the carcinogenesis of lung adenocarcinoma. These findings indicate that p190 is a possible molecular target for treatment of lung adenocarcinoma.