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Carcinogenesis Advance Access published online on April 5, 2006
Carcinogenesis, doi:10.1093/carcin/bgl018
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received December 27, 2005
Revised March 2, 2006
Accepted March 14, 2006

CARCINOGENESIS

Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line

Jenifer I. Fenton 1 *, Stephen D. Hursting 2, Susan N. Perkins 3, and Norman G. Hord 4

1 Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD; Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI
2 Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD; Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, MD; Current address: Division of Nutritional Sciences, University of Texas, Austin, TX
3 Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD; Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, MD
4 Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI

* To whom correspondence should be addressed.
Jenifer I. Fenton, E-mail: imigjeni{at}msu.edu


  Abstract

Increased visceral adipose tissue results in elevated plasma leptin which are associated with increased risk of a number of obesity-related cancers. However, research is contradictory regarding the role of elevated plasma leptin in colon cancer risk. Having established that leptin induced proliferation in a murine model of preneoplastic (ApcMin/+; IMCE) colon epithelial cells but not normal (Apc+/+; YAMC) cells, we hypothesized that the leptin-associated IMCE cell proliferation was a result of autocrine interleukin-6 (IL-6) production and ensuing IL-6 receptor (IL-6R) signaling. Here we show, for the first time, that leptin induces elevated IL-6 production in IMCE cells, but not YAMC cells. IL-6 treatment induced cell proliferation in IMCE cells, but not YAMC cells, in a concentration-dependent manner from 0.1 to 100 ng/ml (p<0.05). Interleukin-6-induced IMCE cell proliferation was blocked by the addition of a neutralizing anti-IL-6R antibody. In addition, leptin-induced IMCE cell proliferation was blocked by the addition of an anti-IL-6R neutralizing antibody. Further, we elucidate a novel mechanism by which leptin activates TACE/ADAM17-associated IL-6R shedding and trans-IL-6 signaling in IMCE by induction of IL-6 production. IL-6 treatment of IMCE cells was associated with STAT3, ERK, p38, MEK and JAK2 activation and assocaited STAT3 nuclear activation and translocation. These data implicate leptin-induced IL-6 production, signaling and subsequent STAT3 activation as early events promoting the survival/proliferation of colon epithelial preneoplastic cells. The elucidation of the leptin-initiated mechanism of preneoplastic cell proliferation establishes a biologically plausible link between the adipoctye-specific cytokine leptin and obesity-associated colon cancer.

Keywords: Leptin; colon; IL-6; cancer; IMCE.
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