6533b85bfe1ef96bd12bb596
RESEARCH PRODUCT
Suppressor of cytokine signaling 3 sensitizes anaplastic thyroid cancer to standard chemotherapy
Francesco DieliGiuseppe BuscemiRuggero De MariaVincenzo EternoMaria Giovanna FrancipaneMiriam BiniGaspare GulottaMatilde TodaroGiorgio StassiGregorio ScerrinoValentina Spinasubject
STAT3 Transcription FactorCancer ResearchCancer Research; OncologyDown-RegulationMice NudeSuppressor of Cytokine Signaling Proteinsthyroidcancer spheres cytokines apoptosis chemoterapyMicePhosphatidylinositol 3-KinasesSuppressor of Cytokine Signaling 1 ProteinMedicineAnimalsHumansSOCS3Thyroid NeoplasmsAnaplastic thyroid cancerPhosphorylationThyroid cancerPI3K/AKT/mTOR pathwayAgedSettore MED/04 - Patologia GeneraleJanus kinase 1business.industrySuppressor of cytokine signaling 1Settore BIO/16 - Anatomia UmanaGene Transfer TechniquesCancerJanus Kinase 1Middle Agedmedicine.diseaseXenograft Model Antitumor AssaysSettore MED/18 - Chirurgia GeneraleOncologyDrug Resistance NeoplasmSuppressor of Cytokine Signaling 3 ProteinImmunologyCancer researchFemalebusinessJanus kinaseSTAT6 Transcription FactorProto-Oncogene Proteins c-aktdescription
We previously showed that cancer cells from papillary, follicular, and anaplastic thyroid carcinomas produce interleukin-4 and interleukin-10, which counteract the cytotoxic activity of conventional chemotherapy through the up-regulation of antiapoptotic molecules. Here, we identify Janus kinase/signal transducers and activators of transcription (STAT) and phosphatidyl inositol 3-kinase (PI3K)/AKT as the down-stream pathways through which these cytokines confer resistance to cell death in thyroid cancer. We found that the absence of suppressors of cytokine signaling (SOCS) molecules allows the propagation of the survival signaling. Exogenous expression of SOCS1, SOCS3, and SOCS5 in the highly aggressive anaplastic thyroid cancer cells reduces or abolishes STAT3 and 6 phosphorylation and PI3K/Akt pathway activation resulting in alteration in the balance of proapoptotic and antiapoptotic molecules and sensitization to chemotherapeutic drugs in vitro. Likewise, exogenous expression of SOCS3 significantly reduces tumor growth and potently enhances the efficacy of chemotherapy in vivo. Our results indicate that SOCS3 regulation of cytokines-prosurvival programs might represent a new strategy to overcome the resistance to chemotherapy-induced cell death of thyroid cancer. We previously showed that cancer cells from papillary, follicular, and anaplastic thyroid carcinomas produce interleukin-4 and interleukin-10, which counteract the cytotoxic activity of conventional chemotherapy through the up-regulation of antiapoptotic molecules. Here, we identify Janus kinase/signal transducers and activators of transcription (STAT) and phosphatidyl inositol 3-kinase (PI3K)/AKT as the down-stream pathways through which these cytokines confer resistance to cell death in thyroid cancer. We found that the absence of suppressors of cytokine signaling (SOCS) molecules allows the propagation of the survival signaling. Exogenous expression of SOCS1, SOCS3, and SOCS5 in the highly aggressive anaplastic thyroid cancer cells reduces or abolishes STAT3 and 6 phosphorylation and PI3K/Akt pathway activation resulting in alteration in the balance of proapoptotic and antiapoptotic molecules and sensitization to chemotherapeutic drugs in vitro. Likewise, exogenous expression of SOCS3 significantly reduces tumor growth and potently enhances the efficacy of chemotherapy in vivo. Our results indicate that SOCS3 regulation of cytokines-prosurvival programs might represent a new strategy to overcome the resistance to chemotherapy-induced cell death of thyroid cancer.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2009-01-01 |