title: Prohibitin attenuates colitis-associated tumorigenesis in mice by modulating p53 and STAT3 apoptotic responses.
abstract: Although inflammatory bowel disease is associated with higher risk of colorectal cancer, the precise pathogenic mechanisms underlying this association are not completely understood. Prohibitin 1 (PHB), a protein implicated in the regulation of proliferation, apoptosis, and transcription, is decreased in intestinal inflammation. In this study, we have established a key function for PHB in mediating colitis-associated cancer. Wild-type and transgenic (Tg) mice specifically overexpressing PHB in intestinal epithelial cells were subjected to a classical two-stage protocol of colitis-associated carcinogenesis. In addition, wild-type and p53 null human cell models were used to assess PHB interaction with STAT3 and p53. Wild-type mice exhibited decreased mucosal PHB protein expression during colitis-associated carcinogenesis. Tg mice exhibited decreased susceptibility in a manner associated with increased apoptosis, p53, Bax, and Bad expression plus decreased Bcl-xL and Bcl-2 expression. PHB overexpression in wild-type but not p53 null human cells increased expression of Bax, Bad, and caspase-3 cleavage. In wild-type p53 cells, PHB overexpression decreased basal and interleukin-6-induced STAT3 activation and expression of the STAT3 responsive genes Bcl-xL and Bcl-2. PHB coimmunoprecipitated with phospho-STAT3 in addition to p53 in cultured cell lysates and colon mucosa. This is the first study to show interaction between PHB and STAT3 in vivo. In summary, our findings suggest that PHB protects against colitis-associated cancer by modulating p53- and STAT3-mediated apoptosis. Modulation of PHB expression in intestinal epithelial cells may offer a potential therapeutic approach to prevent colitis-associated carcinogenesis.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas 75246, USA.
authors.forename: Arwa S
authors.initials: AS
authors.lastname: Kathiria
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rhees
authors.forename: Erin
authors.initials: E
authors.lastname: Hotchkiss
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Robert M
authors.initials: RM
authors.lastname: Genta
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Rhonda F
authors.initials: RF
authors.lastname: Souza
authors.forename: Arianne L
authors.initials: AL
authors.lastname: Theiss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018938:Caco-2 Cells; D003092:Colitis / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000091402:Prohibitins; D012097:Repressor Proteins / Q000096:biosynthesis*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C000717328:PHB protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016159:Tumor Suppressor Protein p53