title: Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.
abstract: Proton radiotherapy is becoming more common as protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared with conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole-body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIRs), which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence-associated gene (P19Arf), are markedly increased. Following these changes, loss of Casein kinase Iα and induction of chronic DNA damage and TP53 mutations are increased compared with X-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-ethyl amide (CDDO-EA), reduces proton irradiation-associated SIR and tumorigenesis. Thus exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Bozeman
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kaisani
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Richardson
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Wright
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: J W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D000375:Aging / Q000235:genetics*; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D004249:DNA Damage; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000528:radiation effects; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D061766:Proton Therapy / Q000379:methods*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014916:Whole-Body Irradiation
chemical_list: C518860:2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid ethyl amide; D016159:Tumor Suppressor Protein p53; D009828:Oleanolic Acid