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

Notsuda,Hirotsugu; Sakurada,Akira; Endo,Chiaki; Okada,Yoshinori; Horii,Akira; Shima,Hiroshi; Kondo,Takashi

doi:10.3892/ijo.2013.2096

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

Authors:
- Hirotsugu Notsuda
- Akira Sakurada
- Chiaki Endo
- Yoshinori Okada
- Akira Horii
- Hiroshi Shima
- Takashi Kondo
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Affiliations: Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan, Department of Molecular Pathology, Tohoku University School of Medicine, Sendai 980-8574, Japan, Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan
Published online on: September 13, 2013 https://doi.org/10.3892/ijo.2013.2096
Pages: 1569-1577

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Abstract

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.

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