title: Adiponectin and metformin additively attenuate IL1β-induced malignant potential of colon cancer.
abstract: Both adiponectin (AD) and metformin (Met) have been proposed to downregulate cell proliferation of colon cancer cells, but whether their effect might be additive has not been studied to date. Genetic studies in humans have suggested an important role for interleukin 1β (IL1β) in cancer pathogenesis. Direct evidence that IL1β contributes to the development of colon cancer has not yet been fully confirmed and no previous studies have evaluated how IL1β may interact with AD and/or Met to regulate malignant potential and intracellular signaling pathways in human and mouse colon cancer cells. We conducted in vitro studies using human (LoVo) and mouse (MCA38) colon cancer cell lines to evaluate whether AD and Met alone or in combination may antagonize IL1β-regulated malignant potential in human and mouse colon cancer cell lines. IL1β increased malignant potential and regulated the expression of tumor suppressor (p53) and cell cycle regulatory genes (p21, p27, and cyclin E2) in human and mouse colon cancer cell lines. These effects were reversed by co-administration of AD and/or Met and were additively altered by AD and Met in combination in a STAT3- and AMPK/LKB1-dependent manner. We also observed using fluorescence activated cell sorter analysis that IL1β-regulated cell cycle progression is altered by AD and Met alone or in combination. Our novel mechanistic studies provide evidence for an important role for IL1β in colon cancer and suggest that AD and/or Met might be useful agents in the management or chemoprevention of IL1β-induced colon carcinogenesis.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, JP9B52A, 150 South Huntington Avenue, Boston, Massachusetts 02130, USA.
authors.forename: Hyun-Seuk
authors.initials: HS
authors.lastname: Moon
authors.forename: Christos S
authors.initials: CS
authors.lastname: Mantzoros
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D053583:Interleukin-1beta / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D052242:Adiponectin; D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases
keywords: LKB1; adiponectin; colon cancer; interleukin 1β; malignant potential; metformin