title: XIAP as a radioresistance factor and prognostic marker for radiotherapy in human rectal adenocarcinoma.
abstract: A differential responsiveness of patients to ionizing radiation is observed after preoperative radiotherapy for rectal adenocarcinoma that might be related, in part, to an apoptosis defect. To establish if proteins of the apoptotic cascades [pro-apoptotic: active caspase 3, 8, and 9 and DIABLO (direct inhibitor of apoptosis-binding protein with low pI); anti-apoptotic: XIAP (X-linked inhibitor of apoptosis)] are involved, we analyzed their profile in radioresistant (SW480) and radiosensitive (SW48) human colorectal cell lines. We demonstrated that, after irradiation, the SW48 cells increased the expression of the pro-apoptotic proteins, whereas the SW480 cells increased the expression of the anti-apoptotic protein XIAP. Moreover, XIAP knockdown in SW480 cells enhanced the basal and radiation-induced apoptotic index; the propensity of the SW480 cells to undergo apoptosis after radiation was higher compared with SW48 cells. In a translational study of 38 patients with rectal carcinoma, we analyzed the apoptotic profile for tumor and noncancerous tissue for each biopsy specimen using IHC. According to their response to preoperative radiotherapy, patients were classified into two groups: responsive and nonresponsive. Although no difference in expression of caspase 3, 8, or 9 was observed in the tumor/normal tissue ratio between responsive and nonresponsive patients, the ratio decreased for DIABLO and increased for XIAP. In conclusion, inhibition of XIAP rescues cellular radiosensitivity and both DIABLO and XIAP might be potential predictive markers of radiation responsiveness in rectal adenocarcinoma.
authors.affiliation: Service de Gastroentérologie, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre-Bénite, France.
authors.forename: Driffa
authors.initials: D
authors.lastname: Moussata
authors.forename: Souheila
authors.initials: S
authors.lastname: Amara
authors.forename: Bénazir
authors.initials: B
authors.lastname: Siddeek
authors.forename: Myriam
authors.initials: M
authors.lastname: Decaussin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hehlgans
authors.forename: Rachel
authors.initials: R
authors.lastname: Paul-Bellon
authors.forename: Françoise
authors.initials: F
authors.lastname: Mornex
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gerard
authors.forename: Pascale
authors.initials: P
authors.lastname: Romestaing
authors.forename: Franz
authors.initials: F
authors.lastname: Rödel
authors.forename: Bernard
authors.initials: B
authors.lastname: Flourie
authors.forename: Mohamed
authors.initials: M
authors.lastname: Benahmed
authors.forename: Claire
authors.initials: C
authors.lastname: Mauduit
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism; D011379:Prognosis; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D012004:Rectal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D053148:Caspase 3; D053181:Caspase 8