The transforming functions of PI3-kinase-gamma are linked to disruption of intercellular adhesion and promotion of cancer cell invasion.
The involvement of phosphoinositide 3-kinases class IA (PI3K-alpha and -beta) in cancer cell proliferation, survival, motility, and invasiveness is now well established. However, the possible contribution of the class IB PI3Kgamma in cancer cell transformation remains to be explored. In this study, we have stably transfected the PI3Kgamma-deficient human colon cancer cell line HCT8/S11 with expression vectors encoding either wild-type PI3Kgamma, its plasma membrane targeted form CAAX-PI3Kgamma, or the PI3Kgamma lipid and protein kinase-dead mutant (CAAX-K832R). We provide evidence that the constitutively active CAAX-PI3Kgamma variant induced collagen type I invasion in HCT8/S11 cells through disruption of cell-cell adhesion, with no apparent impact on cell proliferation and motility. The proinvasive activity of CAAX-PI3K-gamma was abolished by pharmacological inhibitors targeting PI3-K activities (wortmannin), Rho-GTPases, and the Rho-Rho kinase axis (C3T exoenzyme and Y27632, respectively). Conversely, the wild-type PI3Kgamma and its double mutant CAAX-K832R were ineffective on cancer cell invasion measured under control or stimulated conditions operated with the proinvasive agents leptin and intestinal trefoil factor. Taken together, our data indicate that PI3Kgamma exerts transforming functions via several mechanisms in human colon epithelial cancer cells, including alterations of homotypic cell-cell adhesion and induction of collagen type I invasion through canonical proinvasive pathways.
Attoub
Samir
S
INSERM U 673, Molecular and Clinical Oncology of Solid Tumors, University Pierre et Marie Curie Paris VI, Hospital Saint-Antoine, Paris, France. samir.attoub@uaeu.ac.ae
De Wever
Olivier
O
Bruyneel
Eric
E
Mareel
Marc
M
Gespach
Christian
C
D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human