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Rac1 and Cdc42 differentially modulate cigarette smoke-induced airway cell migration through p120-catenin-dependent and -independent pathways.

Abstract
The adherens junction protein p120-catenin (p120ctn) shuttles between E-cadherin-bound and cytoplasmic pools to regulate E-cadherin/catenin complex stability and cell migration, respectively. When released from the adherens junction, p120ctn promotes cell migration through modulation of the Rho GTPases Rac1, Cdc42, and RhoA. Accordingly, the down-regulation and cytoplasmic mislocalization of p120ctn has been reported in all subtypes of lung cancers and is associated with grave prognosis. Previously, we reported that cigarette smoke induced cytoplasmic translocation of p120ctn and cell migration, but the underlying mechanism was unclear. Using primary human bronchial epithelial cells exposed to smoke-concentrated medium (Smk), we observed the translocation of Rac1 and Cdc42, but not RhoA, to the leading edge of polarized and migrating human bronchial epithelial cells. Rac1 and Cdc42 were robustly activated by smoke, whereas RhoA was inhibited. Accordingly, siRNA knockdown of Rac1 or Cdc42 completely abolished Smk-induced cell migration, whereas knockdown of RhoA had no effect. p120ctn/Rac1 double knockdown completely abolished Smk-induced cell migration, whereas p120ctn/Cdc42 double knockdown did not. These data suggested that Rac1 and Cdc42 coactivation was essential to smoke-promoted cell migration in the presence of p120ctn, whereas migration proceeded via Rac1 alone in the absence of p120ctn. Thus, Rac1 may provide an omnipotent therapeutic target in reversing cell migration during the early (intact p120ctn) and late (loss of p120ctn) stages of lung carcinogenesis.
AuthorsLili Zhang, Marianne Gallup, Lorna Zlock, Walter E Finkbeiner, Nancy A McNamara
JournalThe American journal of pathology (Am J Pathol) Vol. 182 Issue 6 Pg. 1986-95 (Jun 2013) ISSN: 1525-2191 [Electronic] United States
PMID23562274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Catenins
  • Culture Media, Conditioned
  • RAC1 protein, human
  • RNA, Small Interfering
  • Smoke
  • RHOA protein, human
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein
  • Delta Catenin
Topics
  • Bronchi (cytology, drug effects, metabolism)
  • Catenins (genetics, physiology)
  • Cell Movement (drug effects, physiology)
  • Cell Transformation, Neoplastic (genetics)
  • Cells, Cultured
  • Culture Media, Conditioned (pharmacology)
  • Epithelial Cells (drug effects, physiology)
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms (metabolism, pathology)
  • RNA, Small Interfering (genetics)
  • Signal Transduction (physiology)
  • Smoke
  • Tobacco
  • cdc42 GTP-Binding Protein (genetics, metabolism, physiology)
  • rac1 GTP-Binding Protein (genetics, metabolism, physiology)
  • rhoA GTP-Binding Protein (metabolism)
  • Delta Catenin

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