Anticancer agents sensitize osteosarcoma cells to TNF-related apoptosis-inducing ligand downmodulating IAP family proteins.
Although TNF-related apoptosis-inducing ligand (TRAIL) usually induces cell death in tumor cells, there are some tumor cell types that are resistant to its apoptogenic effects. Some chemotherapeutic drugs, however, can sensitize resistant cancer cells to TRAIL by either upregulating surface TRAIL death receptor expression or by modulating intracellular signalling pathways emanating from TRAIL receptors. U2OS human osteosarcoma cells express TRAIL-R2 but are resistant to TRAIL-induced apoptosis. however, the genotoxic drugs, Doxorubicin and Cisplatin, are able to sensitize U2OS cells to TRAIL, without affecting their surface expression of either death or decoy TRAIL receptors. We demonstrate that Doxorubicin and Cisplatin downmodulate X-IAP, while not affecting FLIP levels in U2OS cells. Selective downmodulation of X-IAP protein synthesis by specific small interference RNA transfection induced a sensitization of U2OS cells to TRAIL comparable to that induced by pharmacological treatment with genotoxic drugs. TRAIL-R2 downmodulation by siRNAs completely abolished the TRAIL-induced apoptosis of genotoxin-treated U2OS cells. Our findings demonstrate that Doxorubicin and Cisplatin do not sensitize U2OS osteosarcoma cells to TRAIL by surface receptor modulation but rather by the removal of the intracellular signalling inhibition generated by X-IAP, suggesting a foreseeable relevant advantage to the therapy of these tumors by the combined regimen of genotoxin-based chemotherapy and TRAIL.
Mirandola
Prisco
P
Department of Anatomy, Pharmacology and Forensic Medicine, Human Anatomy Section, University of Parma, 43100 Parma, Italy.
Sponzilli
Ivonne
I
Gobbi
Giuliana
G
Marmiroli
Sandra
S
Rinaldi
Laura
L
Binazzi
Roberto
R
Piccari
Gabriella Giuliani
GG
Ramazzotti
Giulia
G
Gaboardi
Gian Carlo
GC
Cocco
Lucio
L
Vitale
Marco
M
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; D004317:Doxorubicin; D002945:Cisplatin