Adiponectin blocks multiple signaling cascades associated with leptin-induced cell proliferation in ApcMin/+ colon epithelial cells
Version of Record online: 13 MAR 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 122, Issue 11, pages 2437–2445, 1 June 2008
How to Cite
Fenton, J. I., Birmingham, J. M., Hursting, S. D. and Hord, N. G. (2008), Adiponectin blocks multiple signaling cascades associated with leptin-induced cell proliferation in ApcMin/+ colon epithelial cells. Int. J. Cancer, 122: 2437–2445. doi: 10.1002/ijc.23436
- Issue online: 25 MAR 2008
- Version of Record online: 13 MAR 2008
- Manuscript Accepted: 19 DEC 2007
- Manuscript Received: 31 MAY 2007
- National Cancer Institute. Grant Number: R03CA130033
- Michigan Agricultural Experiment Station
- colon cancer;
- epithelial cell;
We previously demonstrated that leptin, an adipose-derived hormone, induces cell proliferation in a model of preneoplastic (IMCE (ApcMin/+), but not normal (YAMC (Apc+/+), colon epithelial cells by inducing autocrine IL-6 production and trans-IL-6 signaling. Low serum adiponectin is associated with colon, prostate and breast cancer. Adiponectin is secreted by white adipose tissue; the levels of adiponectin in the blood decrease as body mass index (and leptin) increases. In our study, we tested whether murine recombinant globular adiponectin (gArcp30) could modulate leptin-induced cell proliferation, autocrine IL-6 production, trans-IL-6 signaling and other leptin-induced cell signaling events previously observed in IMCE cells but not YAMC cells. Under serum-free conditions, adiponectin (1 μg/ml) inhibited leptin-induced autocrine IL-6 production, soluble IL-6 receptor shedding, trans-IL-6 signaling and subsequent STAT3 phosphorylation in IMCE cells. Adiponectin inhibited leptin-induced cell proliferation in the IMCE cells and this inhibition was associated with IκB-α phosphorylation, IκB-α degradation and decreased NF-κB p65 DNA activation and binding. These data indicate that adiponectin acts on preneoplastic colon epithelial cells to regulate cell growth via 2 distinct pathways inhibiting leptin-induced NF-κB-dependent autocrine IL-6 production and trans-IL-6 signaling. We hypothesize that adiponectin may be an important regulator of colon epithelial cell homeostasis by linking the observed reduced risk for cancer in populations with high serum adiponectin concentrations to specific mechanisms of cell number homeostasis in a model of preneoplastic colon epithelial cells. These data may have broad implications for diet and lifestyle strategies for the prevention and treatment of obesity-associated cancers. © 2008 Wiley-Liss, Inc.