title: Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line.
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 (Apc(Min/+); 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 in YAMC cells. IL-6 treatment induced cell proliferation in IMCE cells, but not in 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 associated 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 adipocyte-specific cytokine leptin and obesity-associated colon cancer.
authors.affiliation: Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892-7361, USA. imigjeni@msu.edu
authors.forename: Jenifer I
authors.initials: JI
authors.lastname: Fenton
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.forename: Susan N
authors.initials: SN
authors.lastname: Perkins
authors.forename: Norman G
authors.initials: NG
authors.lastname: Hord
mesh_terms: D051722:ADAM Proteins / Q000187:drug effects / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D017491:Genes, APC; D015850:Interleukin-6 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D053614:Janus Kinase 2; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000503:physiopathology; D011230:Precancerous Conditions / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D020738:Leptin; D011518:Proto-Oncogene Proteins; D019947:Receptors, Interleukin-6; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C515447:leptin receptor, mouse; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse