title: MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target.
abstract: MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+CD44+cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Y H
authors.initials: YH
authors.lastname: Sheng
authors.affiliation: Cancer Biology Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: S Z
authors.initials: SZ
authors.lastname: Hasnain
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Tong
authors.affiliation: Molecular Basis of Disease Program, School of Medical Sciences, Griffith University, Gold Coast Campus, Southport, Queensland, Australia.
authors.forename: D T
authors.initials: DT
authors.lastname: Clarke
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.|Inflammatory Bowel Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Lourie
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.|Inflammatory Bowel Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Oancea
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: K Y
authors.initials: KY
authors.lastname: Wong
authors.affiliation: Wesley Hospital, Auchenflower, Australia.
authors.forename: J W
authors.initials: JW
authors.lastname: Lumley
authors.affiliation: Inflammatory Bowel Diseases Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: T H
authors.initials: TH
authors.lastname: Florin
authors.affiliation: Mucosal Immunology, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia.|Centre for Animal Biotechnology, School of Veterinary and Agricultural Science, University of Melbourne, Melbourne, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Sutton
authors.affiliation: Cancer Biology Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: J D
authors.initials: JD
authors.lastname: Hooper
authors.affiliation: Molecular Basis of Disease Program, School of Medical Sciences, Griffith University, Gold Coast Campus, Southport, Queensland, Australia.
authors.forename: N A
authors.initials: NA
authors.lastname: McMillan
authors.affiliation: Inflammatory Disease Biology and Therapeutics Group-Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: McGuckin
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D000954:Antigens, Surface; D000964:Antimetabolites, Antineoplastic; C494811:BCL2L1 protein, human; C063487:Ly64 protein, mouse; C000621991:MICOS13 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051020:bcl-X Protein; D004815:Epidermal Growth Factor; D005472:Fluorouracil