title: High levels of X-linked Inhibitor-of-Apoptosis Protein (XIAP) are indicative of radio chemotherapy resistance in rectal cancer.
abstract: BACKGROUND
  The mainstay of treatment in rectal cancer is neoadjuvant radio chemotherapy prior to surgery, in an attempt to downstage the tumour, allowing for more complete removal during surgery. In 40 % of cases however, this neoadjuvant radio chemotherapy fails to achieve tumour regression, partly due insufficient apoptosis signaling. X-linked Inhibitor of Apoptosis Protein (XIAP) is an anti-apoptotic protein that has been reported to contribute to disease progression and chemotherapy resistance.
  
  
  METHODS
  We obtained rectal biopsy normal and matched tumour tissue from 29 rectal cancer patients with varying degrees of tumour regression, and using Western blot, examined anti-apoptotic XIAP and pro-apoptotic Smac protein levels in these tissues, with the aim to examine whether disturbed XIAP/Smac levels may be an indicator of neoadjuvant radio chemotherapy resistance. Expression of inhibitor of apoptosis proteins cIAP-1 and cIAP-2 was also examined.
  
  
  RESULTS
  We found that levels of XIAP increased in accordance with the degree of radio chemotherapy resistance of the tissue. Levels of this protein were also significantly higher in tumour tissue, compared to matched normal tissue in highly resistant tissue. In contrast, Smac protein levels did not increase with radio chemotherapy resistance, and the protein was similarly expressed in normal and tumour tissue, indicating a shift in the balance of these proteins. Post treatment surgical resection tissue was available for 8 patients. When we compared matched tissue pre- and post- radio chemotherapy we found that XIAP levels increased significantly during treatment in both normal and tumour tissue, while Smac levels did not change. cIAP-1 and cIAP-2 levels were not differentially expressed in varying degrees of radio chemotherapy resistance, and neoadjuvant therapy did not alter expression of these proteins.
  
  
  CONCLUSIONS
  These data indicate that disturbance of the XIAP/Smac balance may be a driver of radio chemotherapy resistance, and hence high levels of XIAP may be a useful indicator of neoadjuvant radio chemotherapy resistance in rectal cancer. Moreover, as XIAP levels increase with radio chemotherapy it is possible that a subset of more resistant tumour cells survive this treatment and may be resistant to further adjuvant treatment. Patients with resistant tumours highly expressing XIAP may benefit from alternative treatment strategies, such as Smac mimetics post neoadjuvant radio chemotherapy.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. lflanagan@rcsi.ie.|Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. lflanagan@rcsi.ie.
authors.forename: L
authors.initials: L
authors.lastname: Flanagan
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. JoanKehoe@rcsi.ie.|Departments of Pathology, Beaumont Hospital, Dublin 9, Ireland. JoanKehoe@rcsi.ie.|Departments of Surgery, Beaumont Hospital, Dublin 9, Ireland. JoanKehoe@rcsi.ie.
authors.forename: J
authors.initials: J
authors.lastname: Kehoe
authors.affiliation: Departments of Pathology, Beaumont Hospital, Dublin 9, Ireland. joannafay@rcsi.ie.
authors.forename: J
authors.initials: J
authors.lastname: Fay
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. ornabacon@rcsi.ie.
authors.forename: O
authors.initials: O
authors.lastname: Bacon
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. andreaslindner@rcsi.ie.|Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. andreaslindner@rcsi.ie.
authors.forename: A U
authors.initials: AU
authors.lastname: Lindner
authors.affiliation: Departments of Pathology, Beaumont Hospital, Dublin 9, Ireland. elainekay@beaumont.ie.
authors.forename: E W
authors.initials: EW
authors.lastname: Kay
authors.affiliation: Departments of Surgery, Beaumont Hospital, Dublin 9, Ireland. josephdeasy@beaumont.ie.
authors.forename: J
authors.initials: J
authors.lastname: Deasy
authors.affiliation: Departments of Surgery, Beaumont Hospital, Dublin 9, Ireland. deborahmcnamara@netscape.net.
authors.forename: D A
authors.initials: DA
authors.lastname: McNamara
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. prehn@rcsi.ie.|Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. prehn@rcsi.ie.
authors.forename: J H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D059248:Chemoradiotherapy; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D011836:Radiation Tolerance / Q000502:physiology*; D012004:Rectal Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000628:therapy; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D005472:Fluorouracil