Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, Rho-, and Rac-dependent signaling pathways

Leptin plays a key role regulating food intake, body weight and fat mass. T hese critical parameters are associated with an increased risk for digestiv e and mammary gland cancer in the Western population. Here we determined wh ether leptin contributes to the invasive phenotype of colonic and kidney ep ithelial cells at various stages of the neoplastic progression. First, lept in potently (EC50 10-30 ng/ml) induces invasion of collagen gels by premali gnant familial adenomatous colonic cells PC/AA/C1 and nontumorigenic MDCK k idney epithelial cells, their src-transformed counterparts, and the human a denocarcinoma colonic cells LoVo and HCT-8/S11. Leptin and its Ob-Rb recept ors were consistently identified by RT-PCR and immunoblotting in these cell , lines, as well as in human colonic epithelial crypts, polyps, colonic tum or resections, and adjacent mucosa. Leptin-induced invasion was effectively blocked by pharmacological inhibitors of several downstream signaling path ways involved in cell transformation, namely, JAK2 tyrosine kinase (AG490), phosphoinositide PI3'-kinase (wortmannin and LY294002), mTOR kinase (rapam ycin), and protein kinases C (GF109203X, Go6976). Accordingly, leptin induc es transient elevation of the PI3'-kinase Lipid products in JAK2 immunoprec ipitates prepared from parental MDCK cells. The leptin effect on invasion w as potentiated by the activated form of the small GTPase RhoA and was abrog ated by dominant negative mutants of RhoA, Rad, and the p110 alpha of PI3'- K. Our data indicate that leptin may exert a local and beneficial effect on migration of normal colonic epithelial cells and reparation of the inflame d or wounded digestive mucosa. We also emphasize a new role for leptin, lin king- the nutritional and body fat status to digestive cancer susceptibilit y by stimulating the invasive capacity of colonic epithelial cells at early stages of neoplasia. This finding has potential clinical implications for colon cancer progression and management of obesity.-Attoub, S., Noe, V., Pi rola, L., Bruyneel, E., Chastre, E., Mareel, M., Wymann, M. P., Gespach, C. Leptin promotes invasiveness of kidney and colonic epithelial cells via ph osphoinositide 3-kinase-, Rho-, and pac-dependent signaling pathways.