Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal‐transduction pathways

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 leptininduced 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.

Self-reported and measured anthropometric data and risk of colorectal cancer in the EPIC–Norfolk study

“…47,49,50 Experimental studies have also shown that leptin, related to the amount of adipose tissue, is increased by excessive energy intake 51 and promotes human colonic cell proliferation and invasiveness in colon cancer. 52,53 In our study, significantly increased CRC risk with obesityrelated anthropometric variables was confined to women. This finding is in contrast with the results from previous studies including several meta-analyses that have shown that obese men, estimated by BMI, are more likely to develop CRC than obese women.…”

Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice

“…40 Leptin also modulates the proliferation of colon adenocarcinoma cancer cells LS174T and HM7; this process possibly takes place through Src and PI3K signaling, which is known to promote colon carcinogenesis and metastasis. 41 Other in vitro studies have suggested that these hormones stimulate the PI3K/Akt pathway and induce the phosphorylation of ERK pathways, thus activating these signaltransduction pathways associated with cell growth. 42,43 The compensatory hyperinsulinemia in obesity also leads to the release of intracellular mediators involved in growth factor signaling, which activate proto-oncogene p21Ras.…”

The Src/PI3K/Akt signal pathway may play a key role in decreased drug efficacy in obesity‐associated cancer

“…The Src/PI3K/Akt pathway is highly activated by multiple cancer risk factors which are elevated in obesity [Jaffe and Schwartz, 2008;Huang and Chen, 2009b]. These factors include increased blood levels of insulin, IGF-1, leptin, TNF-alpha, and IL-6.…”

“…These factors include increased blood levels of insulin, IGF-1, leptin, TNF-alpha, and IL-6. These factors have been demonstrated to activate Src/PI3K/Akt to promote carcinogenesis [Jaffe and Schwartz, 2008;Roberts et al, 2009;Huang and Chen, 2009b]. In addition, decreased blood level of adiponectin in obesity also contributes to the action of the pathway as adiponectin can block insulin and leptin [Fujisawa et al, 2008;Huang and Chen, 2009a].…”