6533b873fe1ef96bd12d4e1c
RESEARCH PRODUCT
Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4
A. Di StefanoM. Perez AleaYlenia LombardoFlora IovinoC Di BernardoHenning WalczakGerolama CondorelliMaria Giovanna FrancipaneAntonino AgrusaPatrizia CammareriGiorgio StassiMatilde Todarosubject
AdultMaleProgrammed cell deathLung NeoplasmsTime Factorsapoptosis interleukin-4 cancer stem cells cancer chemiotherapy cytokinesCASP8 and FADD-Like Apoptosis Regulating Proteinbcl-X ProteinAntineoplastic AgentsApoptosisBreast NeoplasmsBiologyTNF-Related Apoptosis-Inducing LigandTumor Cells CulturedmedicineHumansAutocrine signallingMolecular BiologyInterleukin 4AgedCell ProliferationSettore MED/04 - Patologia GeneraleCell DeathDose-Response Relationship DrugCell growthCarcinomaIntracellular Signaling Peptides and ProteinsAntibodies MonoclonalInterleukin-4 Receptor alpha SubunitCorrectionCancerCell BiologyMiddle AgedPhosphoproteinsmedicine.diseaseUp-RegulationCell biologyAutocrine CommunicationProto-Oncogene Proteins c-bcl-2Drug Resistance NeoplasmApoptosisColonic NeoplasmsCancer cellFemaleInterleukin-4Interleukin-4 Cancer stem cellsSignal transductionApoptosis Regulatory ProteinsSignal Transductiondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2008-01-19 |