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INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, and IFR65, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France;
* The Laboratory of Experimental Cancerology, Ghent University, B-9000 Gent, Belgium; and
Institute of Biochemistry, CH-1700, Fribourg, Switzerland
1Correspondence: INSERM Unit U482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. E-mail: gespach{at}st-antoine.inserm.fr
Leptin plays a key role regulating food intake, body weight and fat
mass. These critical parameters are associated with an increased risk
for digestive and mammary gland cancer in the Western population. Here
we determined whether leptin contributes to the invasive phenotype of
colonic and kidney epithelial cells at various stages of the neoplastic
progression. First, leptin potently (EC50 = 10–30
ng/ml) induces invasion of collagen gels by premalignant familial
adenomatous colonic cells PC/AA/C1 and nontumorigenic MDCK kidney
epithelial cells, their src-transformed counterparts, and the human
adenocarcinoma colonic cells LoVo and HCT-8/S11. Leptin and its Ob-Rb
receptors were consistently identified by RT-PCR and immunoblotting in
these cell lines, as well as in human colonic epithelial crypts,
polyps, colonic tumor resections, and adjacent mucosa. Leptin-induced
invasion was effectively blocked by pharmacological inhibitors of
several downstream signaling pathways involved in cell transformation,
namely, JAK2 tyrosine kinase (AG490), phosphoinositide PI3'-kinase
(wortmannin and LY294002), mTOR kinase (rapamycin), and protein kinases
C (GF109203X, Gö6976). Accordingly, leptin induces transient
elevation of the PI3'-kinase lipid products in JAK2 immunoprecipitates
prepared from parental MDCK cells. The leptin effect on invasion was
potentiated by the activated form of the small GTPase RhoA and was
abrogated by dominant negative mutants of RhoA, Rac1, and the p110
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 inflamed or wounded digestive mucosa. We also
emphasize a new role for leptin, linking the nutritional and body fat
status to digestive cancer susceptibility 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., Pirola,
L., Bruyneel, E., Chastre, E., Mareel, M., Wymann, M. P., Gespach,
C. Leptin promotes invasiveness of kidney and colonic epithelial cells
via phosphoinositide 3-kinase-, Rho-, and Rac-dependent signaling
pathways.
Key Words: wortmannin • PI3'-kinase • MDCK cells • leptin signaling • pertussis toxin
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