Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4.
We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2. Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel treatment for epithelial cancers.
Todaro
M
M
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Lombardo
Y
Y
Francipane
M G
MG
Alea
M Perez
MP
Cammareri
P
P
Iovino
F
F
Di Stefano
A B
AB
Di Bernardo
C
C
Agrusa
A
A
Condorelli
G
G
Walczak
H
H
Stassi
G
G
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D019898:Autocrine Communication; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051020:bcl-X Protein / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C508598:IL4 protein, human; C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; D015847:Interleukin-4