title: Elevated XIAP expression alone does not confer chemoresistance.
abstract: BACKGROUND
  In various tumour types, elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been observed and XIAP targeting in diverse tumour entities enhanced the susceptibility to chemotherapeutic agents. Therefore, XIAP has been described and reviewed repeatedly as a chemoresistance factor in different tumour entities. However, rather than being an adverse prognostic marker, recent data suggest that elevated XIAP expression may be associated with a favourable clinical outcome. These somewhat conflicting findings, and the fact that in early studies XIAP suppressed apoptosis only when expressed transiently at levels far in excess of its physiological concentration, argue that the function of XIAP as an anti-apoptotic factor in tumour cells is both more complex and diverse than previously appreciated.
  
  
  METHODS
  To better understand the impact of long-term elevated XIAP expression on resistance to chemotherapy, we generated cell lines stably overexpressing XIAP. The role of mitochondria was examined by stable expression of Bcl2 or stable knockdown of second mitochondria-derived activator of caspase (SMAC) in combination with up- or downregulation of XIAP expression.
  
  
  RESULTS
  Our data show that long-term expression of XIAP at concentrations comparable to that in tumour cells (two- to five-fold increase) resulted in little or no resistance towards chemotherapeutic drugs. The XIAP overexpression only in conjunction with stable knockdown of a single XIAP-antagonising factor such as SMAC resulted in severe resistance to cytostatic agents demonstrating XIAP as a potent chemoresistance factor only in cells lacking functional XIAP regulatory circuits.
  
  
  CONCLUSIONS
  Our results demonstrated that elevated XIAP expression alone cannot serve as a predictive marker of chemoresistance. Our data suggest that in order to predict the impact of XIAP on chemosusceptibility for a given tumour entity, the expression levels and functional states of all XIAP modulators need to be taken into account.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstrasse 19-21, 50935 Köln, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Seeger
authors.forename: K
authors.initials: K
authors.lastname: Brinkmann
authors.forename: B
authors.initials: B
authors.lastname: Yazdanpanah
authors.forename: D
authors.initials: D
authors.lastname: Haubert
authors.forename: C
authors.initials: C
authors.lastname: Pongratz
authors.forename: O
authors.initials: O
authors.lastname: Coutelle
authors.forename: M
authors.initials: M
authors.lastname: Krönke
authors.forename: H
authors.initials: H
authors.lastname: Kashkar
mesh_terms: D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D020169:Caspases