FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3K/Akt pathway.
Cancer cell adhesion is traditionally viewed as random, occurring if the cell's receptors match the substrate. Cancer cells are subjected to pressure and shear during growth against a constraining stroma, surgical manipulation, and passage through the venous and lymphatic system. Cells shed into a cavity such as the abdomen postoperatively also experience increased pressure from postoperative edema. Increased extracellular pressure stimulates integrin-mediated cancer cell adhesion via FAK and Src. PI 3-kinase (PI3K) inhibitors (LY294002 or wortmannin), Akt inhibitors, or Akt1 siRNA blocked adhesion stimulated by 15 mmHg pressure in SW620 or primary human malignant colonocytes. Pressure activated PI3K, tyrosine-phosphorylated and membrane-translocated the p85 subunit, and phosphorylated Akt. PI3K inhibitor (LY294002) prevented pressure-stimulated Akt Ser473 and FAK Tyr397, but not FAK576 or Src416 phosphorylation. PP2 inhibited PI3K activity and Akt phosphorylation. FAK siRNA did not affect pressure-induced PI3K activation but blocked Akt phosphorylation. Pressure also stimulated FAK or FAKY397F mutant translocation to the membrane. Akt inhibitor IV blocked pressure-induced Akt and FAK translocation. Pressure activated Src- and PI3K-dependently induced p85 interaction with FAK, and FAK with beta1 integrin. These results delineate a novel force-activated inside-out Src/PI3K/FAK/Akt pathway by which cancer cells regulate their own adhesion. These signals may be potential targets for inhibition of metastatic adhesion.
Thamilselvan
Vijayalakshmi
V
Department of Surgery, John D. Dingell VA Medical Center, 4646 John R. St., Detroit, Michigan 48201-1932, USA.
Craig
David H
DH
Basson
Marc D
MD
D002448:Cell Adhesion; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology*; D004487:Edema; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D016023:Integrins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011312:Pressure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction
D016023:Integrins; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt