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Adiponectin blocks multiple signaling cascades associated with leptin‐induced cell proliferation in Apc Min/+ colon epithelial cells
Author(s) -
Fenton Jenifer I.,
Birmingham Janette M.,
Hursting Stephen D.,
Hord Norman G.
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23436
Subject(s) - autocrine signalling , adiponectin , endocrinology , medicine , leptin , biology , signal transduction , adipose tissue , cell growth , adiponectin receptor 1 , adipokine , microbiology and biotechnology , chemistry , cancer research , receptor , biochemistry , insulin resistance , insulin , obesity
We previously demonstrated that leptin, an adipose‐derived hormone, induces cell proliferation in a model of preneoplastic (IMCE ( Apc Min/+ ), 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.