Suppressor of Cytokine Signaling 3 Sensitizes Anaplastic Thyroid Cancer to Standard Chemotherapy

Abstract

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 upregulation 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. [Cancer Res 2009;69(15):6141-8]

SOCS5 and SOCS6 have similar expression patterns in normal and cancer tissues

“…Previously, shorter N-terminal SOCS members were found to be associated with thyroid cancers by reducing the suppressive action of the activated Jak/Stat pathways [27][28][29]. Our results support the hypothesis that longer N-terminal SOCS members are also associated with thyroid cancer progression.…”

Loss of SOCS3 expression is associated with an increased risk of recurrent disease in breast carcinoma

“…SOCS3 h-KO mice develop hepatocellular carcinoma at an accelerated rate in the model of chemical-induced carcinogenesis (Riehle et al 2008). In vitro, exogenous expression of SOCS3 in the highly aggressive anaplastic thyroid cancer cells reduces STAT3 phosphorylation and PI3K/Akt pathway activation resulting in alteration in the balance of proapoptotic and anti-apoptotic molecules and sensitization to chemotherapeutic drugs (Francipane et al 2009). Likewise, exogenous (Kim et al 2008;Kinjyo et al 2007).…”

Sox6 enhances erythroid differentiation in human erythroid progenitors

“…The TWEEN vector containing human SOCS3 cDNA was kindly provided by Dr M. G. Francipane (University of Palermo, Italy). 22 For transfection, the human SOCS3 promoter region (nucleotide [nt]-393ϩ12) was amplified from genomic DNA with Phusion DNA Polymerase (Finnzymes) and cloned into the pGL2 reporter vector (Promega). The 70-nt SOCS3 region (nt Ϫ2727 to Ϫ2678) that contained the double Sox6 binding site (wild-type or mutated) was cloned (SacI-NheI sites) upstream of the SOCS3 promoter.…”

“…After 2 weeks, burst-formingunit erythroid, CFU-granulocyte/macrophage, and CFU-granulocyte/ erythrocyte/monocyte/megakaryocyte (GEMM) colonies were counted, and single colonies (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) for each experiment) were isolated for DNA and RNA extraction.…”