Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal-transduction pathways
Authors: Tamara Jaffe
Betty Schwartz
Journal: International Journal of Cancer (2008)
Discipline: CLINICAL MEDICINE
Keywords: Leptin; signaling pathways; colonic cells; Ob-receptor; mitogen-activated protein kinase pathway
Affiliations: Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot, Israel.

Abstract:  Leptin serum levels are about 5 times higher in obese people than in normal individuals. We aimed at investigating the signaling pathways induced by leptin in the human colonic cell lines LS174T and HM7. Both cells expressed the leptin transmembrane Ob-receptor. Leptin activated the mitogen-activated protein kinase pathway, induced invasion of colonic cells and concomitantly increased the formation of lamellipodial structures. A direct and novel dose- and time-dependent activation of RhoA, Cdc42 and Rac1 by leptin is demonstrated in these aggressive colon cancer cells. The activation of the Rho family of GTPases was amenable to specific inhibition: Wortmannin inhibited leptin-induced Rac1 and Cdc42 activation but did not affect RhoA activation, and inhibited the formation of leptin-induced lamellipodia and cell invasion. The Rac1 inhibitor NSC23766 inhibited only leptin-induced Rac1 activation and concomitantly, lamellipodium formation and cell invasion. The Src kinase inhibitor II (SrcKI-II) exerted a positive effect on RhoA activation, inhibited tyrosine phosphorylation of p190RhoGAP and inhibited leptin-induced Cdc42 activation and leptin-induced lamellopodium formation and cell invasion. The specific JAK2 inhibitor AG490 exerted a positive effect on Rac1 and Cdc42 activation by leptin and concomitantly inhibited RhoA activation. AG490 did not inhibit leptin-induced lamellopodium formation or cell invasion. Our findings clearly indicate that leptin activates PI3K and Src kinase pathways in the metastatic colon cancer cells LS174T and HM7. These signaling pathways induce the activation of Rac1 and Cdc42, lamellopodium formation and concomitantly enhanced cell invasion, but leptin activation of RhoA is not associated with enhanced cell locomotion and invasion. Understanding in-depth the pathways involved in leptin-associated enhanced cell locomotion and invasion may contribute with the design of novel therapeutics to treat obesity-associated advanced colorectal cancer. 

Retracted: No

PubPeer comments:
 Figure 4. * Blue boxes: The bottom panels (loading controls?, not labeled) of Figure 4e (LS174T cells) and Figure 4g (HM7 cells) look unexpectedly similar * Red boxes: The bottom panels (loading controls?, not labeled) of Figure 4i (LS174T cells) and Figure 4k (HM7 cells) look unexpectedly similar ![file] ![file] , 
 Figure 5M. * The blots here look remarkably similar to lanes in Figure 7E of another paper by the same research group, i.e. Liat Abovich Gilad and Betty Schwartz, Journal of Molecular Endocrinology (2007), DOI: 10.1677 jme-06-0040, https: pubpeer.com publications 7D29344FA55E16152AD5FD22CC650A, where they appear to represent very different proteins and experimental conditions. ![file] ,