IL-4 protects tumor cells from anti-CD95 and chemotherapeutic agents via up-regulation of antiapoptotic proteins.
We recently proposed that Th1 and Th2 cytokines exert opposite effects on the pathogenesis and clinical outcome of organ-specific autoimmunity by altering the expression of genes involved in target cell survival. Because a Th2 response against tumors is associated with poor prognosis, we investigated the ability of IL-4 to protect tumor cells from death receptor- and chemotherapy-induced apoptosis. We found that IL-4 treatment significantly reduced CD95 (Fas/APO-1)- and chemotherapeutic drug-induced apoptosis in prostate, breast, and bladder tumor cell lines. Analysis of antiapoptotic protein expression revealed that IL-4 stimulation resulted in up-regulation of cellular (c) FLIP/FLAME-1 and Bcl-x(L). Exogenous expression of cFLIP/FLAME-1 inhibited apoptosis induced by CD95 and to a lesser extent by chemotherapy, while tumor cells transduced with Bcl-x(L) were substantially protected both from CD95 and chemotherapeutic drug stimulation. Moreover, consistent IL-4 production and high expression of both cFLIP/FLAME-1 and Bcl-x(L) were observed in primary prostate, breast, and bladder cancer in vivo. Finally, primary breast cancer cells acquired sensitivity to apoptosis in vitro only in the absence of IL-4. Thus, IL-4 protects tumor cells from CD95- and chemotherapy-induced apoptosis through the up-regulation of antiapoptotic proteins such as cFLIP/FLAME-1 and Bcl-x(L). These findings may provide useful information for the development of therapeutic strategies aimed at restoring the functionality of apoptotic pathways in tumor cells.
Conticello
Concetta
C
Department of Experimental Oncology, Mediterranean Institute of Oncology, Catania, Italy.
Pedini
Francesca
F
Zeuner
Ann
A
Patti
Mariella
M
Zerilli
Monica
M
Stassi
Giorgio
G
Messina
Angelo
A
Peschle
Cesare
C
De Maria
Ruggero
R
D000911:Antibodies, Monoclonal / Q000502:physiology*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002166:Camptothecin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology*; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology*; D051020:bcl-X Protein; D019014:fas Receptor / Q000276:immunology* / Q000502:physiology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; D019014:fas Receptor; D015847:Interleukin-4; D005047:Etoposide; D002166:Camptothecin