cIAP-2 block apoptotic events in bladder cancer cells.
BACKGROUND
The Inhibitors of Apoptosis (IAPs) are negative regulators of apoptosis and their overexpression renders cells resistant to a variety of apoptotic stimuli. We investigated the mRNA expression levels of IAPs in a panel of bladder tumour cells, selected as being sensitive or resistant to death receptor-mediated apoptosis.


METHODS
The mRNA expression of IAPs was quantified in a RNase protection assay (RPA). Apoptosis was induced by recombinant killerTRAIL, agonistic anti-CD95 mAbs or doxorubicin and quantified by TUNEL and MTT assays. Stable expression of cIAP-2 was obtained by retroviral transduction.


RESULTS
The expression of cIAP-2 mRNA was highly correlated with resistance to TRAIL-mediated apoptosis. Overexpression of cIAP-2 conferred resistance to previously sensitive cell lines and made cells less susceptible to doxorubicin. Treatment with doxorubicin in combination with TRAIL or anti-CD95 resulted in a synergistic cytotoxic effect, which was not possible to reverse by overexpression of cIAP-2.


CONCLUSIONS
cIAP-2 is an important regulator of apoptosis in bladder cancer and its overexpression may make tumours less susceptible to therapy involving apoptosis. The combination of immunotherapy and chemotoxic agents may represent a valid strategy to potentiate anti-tumour therapy, in particular treating tumours resisting conventional chemotherapy.
Jönsson
Gun
G
Department of Immunology, Wenner-Gren Institute, Stockholm University, S-106 91 Stockholm, Sweden. gun@imm2.su.se
Paulie
Staffan
S
Grandien
Alf
A
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019014:fas Receptor / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D004317:Doxorubicin