Suppressor of cytokine signaling 3 sensitizes anaplastic thyroid cancer to standard chemotherapy
| Autor: | Francesco Dieli, Giuseppe Buscemi, Ruggero De Maria, Vincenzo Eterno, Maria Giovanna Francipane, Miriam Bini, Gaspare Gulotta, Matilde Todaro, Giorgio Stassi, Gregorio Scerrino, Valentina Spina |
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| Přispěvatelé: | Francipane, MG, Eterno, V, Spina, V, Bini, M, Scerrino, G, Buscemi, G, Gulotta, G, Todaro, M, Dieli, F, De Maria, R, Stassi, G |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
STAT3 Transcription Factor
Cancer Research Oncology Down-Regulation Mice Nude Suppressor of Cytokine Signaling Proteins thyroid cancer spheres cytokines apoptosis chemoterapy Mice Phosphatidylinositol 3-Kinases Suppressor of Cytokine Signaling 1 Protein Medicine Animals Humans SOCS3 Thyroid Neoplasms Anaplastic thyroid cancer Phosphorylation Thyroid cancer PI3K/AKT/mTOR pathway Aged Settore MED/04 - Patologia Generale Janus kinase 1 business.industry Suppressor of cytokine signaling 1 Settore BIO/16 - Anatomia Umana Gene Transfer Techniques Cancer Janus Kinase 1 Middle Aged medicine.disease Xenograft Model Antitumor Assays Settore MED/18 - Chirurgia Generale Drug Resistance Neoplasm Suppressor of Cytokine Signaling 3 Protein Immunology Cancer research Female business Janus kinase STAT6 Transcription Factor Proto-Oncogene Proteins c-akt |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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