title: Expression of a mutant prohibitin from the aP2 gene promoter leads to obesity-linked tumor development in insulin resistance-dependent manner.
abstract: A critical unmet need for the study of obesity-linked cancer is the lack of preclinical models that spontaneously develop obesity and cancer sequentially. Prohibitin (PHB) is a pleiotropic protein that has a role in adipose and immune functions. We capitalized on this attribute of PHB to develop a mouse model for obesity-linked tumor. We achieved this by expressing Y114F-PHB (m-PHB) from the aP2 gene promoter for simultaneous manipulation of adipogenic and immune signaling functions. The m-PHB mice develop obesity in a sex-neutral manner, but only male mice develop impaired glucose homeostasis and hyperinsulinemia similar to transgenic mice expressing PHB. Interestingly, only male m-PHB mice develop histiocytosis with lymphadenopathy, suggesting that metabolic dysregulation or m-PHB alone is not sufficient for the tumor development and that both are required for tumorigenesis. Moreover, ovariectomy in female m-PHB mice resulted in impaired glucose homeostasis, hyperinsulinemia and consequently tumor development similar to male m-PHB mice. These changes were not observed in sham-operated control m-Mito-Ob mice, further confirming the role of obesity-related metabolic dysregulation in tumor development in m-PHB mice. Our data provide a proof-of-concept that obesity-associated hyperinsulinemia promotes tumor development by facilitating dormant mutant to manifest and reveals a sex-dimorphic role of PHB in adipose-immune interaction or immunometabolism. Targeting PHB may provide a unique opportunity for the modulation of immunometabolism in obesity, cancer and in immune diseases.
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: S R
authors.initials: SR
authors.lastname: Ande
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: K H
authors.initials: KH
authors.lastname: Nguyen
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: G P
authors.initials: GP
authors.lastname: Padilla-Meier
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: B L G
authors.initials: BL
authors.lastname: Nyomba
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.|Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Mishra
mesh_terms: D054392:Adipokines / Q000097:blood; D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D050556:Fatty Acid-Binding Proteins / Q000235:genetics*; D005260:Female; D015614:Histiocytosis / Q000209:etiology; D006946:Hyperinsulinism / Q000150:complications; D007333:Insulin Resistance; D000072281:Lymphadenopathy / Q000209:etiology; D008297:Male; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000209:etiology*; D009765:Obesity / Q000150:complications*; D000091402:Prohibitins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D012727:Sex Characteristics
chemical_list: D054392:Adipokines; D018925:Chemokines; D016207:Cytokines; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D000091402:Prohibitins; D012097:Repressor Proteins