Suppressor of cytokine signaling 3 sensitizes anaplastic thyroid cancer to standard chemotherapy.
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.
Francipane
Maria Giovanna
MG
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Eterno
Vincenzo
V
Spina
Valentina
V
Bini
Miriam
M
Scerrino
Gregorio
G
Buscemi
Giuseppe
G
Gulotta
Gaspare
G
Todaro
Matilde
M
Dieli
Francesco
F
De Maria
Ruggero
R
Stassi
Giorgio
G
D000368:Aged; D000818:Animals; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C408990:SOCS5 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019869:Phosphatidylinositol 3-Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D051057:Proto-Oncogene Proteins c-akt