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.