We have reported previously that Bcl-w, a pro-survival member ofthe Bcl-2 family, is expressed in gastric cancer cells, particularly in those with an infiltrative morphology. Functional studies utilizing Bcl-w-overexpressing cells have consistently demonstrated that Bcl-w enhances not only the survivability of the cancer cells, but also their migratory and invasive potentials. The Bcl-w-induced invasive pathway was determined to involve a sequential activation of phosphoinositide 3-kinase (PI3K), Akt, and Sp1, which subsequently results in the expression of metalloproteinase-2 (MMP-2). In this study, we have demonstrated that Bcl-w also induces the urokinase-type plasminogen activator(uPA), which was prevented by treatment with pharmacological inhibitors of PI3K, Akt, or Sp1. These inhibitors also attenuated the ability of Bcl-w to promote cell migration. Similar results were obtained when the actions of MMP-2 and uPA were blocked using their inhibitors or small interfering RNAs (siRNAs), thereby suggesting that these enzymes stimulate migratory signals in this system. Bcl-w overexpression was shown to activate focal adhesion kinase (FAK) in a manner dependent on PI3K, Akt, Sp1, MMP-2, and uPA, and the prevention of FAK action using its siRNAs or dominant negative mutants abolished Bcl-w-induced migration. Overall, it appears that Bcl-w induces both MMP-2 and uPA via the PI3K-Akt-Sp1 pathway, which then promotes cell invasion not only via the degradation of the extracellular matrix, but also via the stimulation of the FAK-dependent migratory pathway.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A3.

Seventh AACR International Conference on Frontiers in Cancer Prevention Research-- Nov 16-19, 2008; Washington, DC