P190A RhoGAP is involved in EGFR pathways and promotes proliferation, invasion and migration in lung adenocarcinoma cells

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

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1569-1577
Number of pages9
JournalInternational journal of oncology
Volume43
Issue number5
DOIs
Publication statusPublished - 2013 Nov

Keywords

  • EGFR
  • Lung cancer
  • P190-A RhoGAP
  • Phosphorylation
  • Therapeutic target

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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