Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells
| Autor: | Sebastiano Bonventre, Mileidys Perez Alea, Lucia Ricci-Vitiani, Giuseppe Di Gesu, Monica Zerilli, Gerolama Condorelli, Ada Maria Florena, Laura Miceli, Ruggero De Maria, Matilde Todaro, Miriam Bini, Giorgio Stassi |
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| Přispěvatelé: | TODARO M, ZERILLI M, RICCI-VITIANI L, BINI M, PEREZ ALEA M, FLORENA AM, MICELI L, CONDORELLI G, BONVENTRE S, DI GESU' G, DE MARIA R, STASSI G |
| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
medicine.medical_treatment NF-KAPPA-B Oligonucleotides C-FLIP CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Suppressor of Cytokine Signaling Proteins SIGNALING COMPLEX Thyroid cancer Tumor CARCINOMA CELLS ANDROGEN RECEPTOR Intracellular Signaling Peptides and Proteins Interleukin HASHIMOTOS-THYROIDITIS Middle Aged Protein-Tyrosine Kinases Interleukin-10 Up-Regulation MALIGNANT GLIOMA-CELLS Interleukin 10 Cytokine Oncology Aged Antibodies Cell Growth Processes Cell Line Tumor Humans Interleukin-4 Janus Kinase 1 Oligonucleotides Antisense Phosphoproteins Repressor Proteins STAT6 Transcription Factor Suppressor of Cytokine Signaling 1 Protein Thyroid Neoplasms fas Receptor medicine.medical_specialty ANTIAPOPTOTIC PROTEINS Cell Line Thyroid carcinoma Settore MED/04 - PATOLOGIA GENERALE Internal medicine medicine Antisense Autocrine signalling Interleukin 4 APOPTOSIS-INDUCING LIGAND business.industry medicine.disease Endocrinology Cancer cell Cancer research business Apoptosis Regulatory Proteins |
| Zdroj: | Cancer research. 66(3) |
| ISSN: | 0008-5472 |
| Popis: | Although CD95 and its ligand are expressed in thyroid cancer, the tumor cell mass does not seem to be affected by such expression. We have recently shown that thyroid carcinomas produce interleukin (IL)-4 and IL-10, which promote resistance to chemotherapy through the up-regulation of Bcl-xL. Here, we show that freshly purified thyroid cancer cells were completely refractory to CD95-induced apoptosis despite the consistent expression of Fas-associated death domain and caspase-8. The analysis of potential molecules able to prevent caspase-8 activation in thyroid cancer cells revealed a remarkable up-regulation of cellular FLIPL (cFLIPL) and PED/PEA-15, two antiapoptotic proteins whose exogenous expression in normal thyrocytes inhibited the death-inducing signaling complex of CD95. Additionally, small interfering RNA FLIP and PED antisense sensitized thyroid cancer cells to CD95-mediated apoptosis. Exposure of normal thyrocytes to IL-4 and IL-10 potently up-regulated cFLIP and PED/PEA-15, suggesting that these cytokines are responsible for thyroid cancer cell resistance to CD95 stimulation. Moreover, treatment with neutralizing antibodies against IL-4 and IL-10 or exogenous expression of suppressor of cytokine signaling-1 of thyroid cancer cells resulted in cFLIP and PED/PEA-15 down-regulation and CD95 sensitization. More importantly, prolonged IL-4 and IL-10 neutralization induced cancer cell growth inhibition and apoptosis, which were prevented by blocking antibodies against CD95 ligand. Altogether, autocrine production of IL-4 and IL-10 neutralizes CD95-generated signals and allows survival and growth of thyroid cancer cells. Thus, IL-4 and IL-10 may represent key targets for the treatment of thyroid cancer. (Cancer Res 2006; 66(3): 1491-9) |
| Databáze: | OpenAIRE |
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