Molecular mechanism underlying the antiproliferative effect of suppressor of cytokine signaling‐1 in non‐small‐cell lung cancer cells

Abstract

Lung cancer (LC) is the major cause of death by cancer and the number of LC patients is increasing worldwide. This study investigated the therapeutic potential of gene delivery using suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of intracellular signaling pathways, for the treatment of LC. To examine the antitumor effect of SOCS-1 overexpression on nonsmall-cell lung cancer (NSCLC) cells, NSCLC cells (A549, LU65, and PC9) were infected with adenovirus-expressing SOCS-1 vector. The cell proliferation assay showed that A549 and LU65, but not PC9, were sensitive to SOCS-1 gene-mediated suppression of cell growth. Although JAK inhibitor I could also inhibit proliferation of A549 and LU65 cells, SOCS-1 gene delivery appeared to be more potent as SOCS-1 could suppress focal adhesion kinase and epidermal growth factor receptor, as well as the JAK ⁄ STAT3 signaling pathway. Enhanced phosphorylation of the p53 protein was detected by means of phospho-kinase array in SOCS-1 overexpressed A549 cells compared with control cells, whereas no phosphorylation of p53 was observed when JAK inhibitor I was used. Furthermore, treatment with adenoviral vector AdSOCS-1 in vivo significantly suppressed NSCLC proliferation in a xenograft model. These results suggest that the overexpression of SOCS-1 gene is effective for antitumor therapy by suppressing the JAK ⁄ STAT, focal adhesion kinase, and epidermal growth factor receptor signaling pathways and enhancing p53-mediated antitumor activity in NSCLC. (Cancer Sci 2013; 104: 1483-1491 L ung cancer is the leading cause of cancer death in Japan and is a growing health epidemic worldwide. (1) Moreover, therapies that can cure metastatic LC have not been yet established, (2,3) so there is an urgent need for the development of novel interventions to cure LC.One of the potential therapeutic targets of NSCLC is STAT3. Constitutively activated STAT3 has been shown to promote tumor cell growth, survival, and tumor angiogenesis, and persistently activated STAT3 has been found in 50% of lung adenocarcinomas. (4) It is thought that STAT3 is activated by JAK, EGFR, or Src family kinases. (5) Among these TYKs, JAK family kinases play an important role in the phosphorylation of STAT3 in NSCLC. (6,7) Dysregulated activation of the JAK ⁄ STAT3 signaling pathway, the major downstream pathway of cytokines such as interleukin-6, has been detected in various cancers including NSCLC. (8) Moreover, it has been recently reported that ruxolitinib, which is a potent and selective JAK1 and JAK2 inhibitor, is associated with marked and durable clinical benefits for patients with myelofibrosis, suggesting that JAK kinases are promising therapeutic targets for cancer. (9) Cytokine signaling pathways are tightly controlled by negative regulatory mechanisms under homeostatic conditions. Suppressors of cytokine signaling family proteins play a role in the negative regulation of cytokine responses by terminating the activation of the JAK ⁄ STAT and other signaling pathways. (10)(11)(12) The SOCS f...

Inhibition of MDR1 in mammary cell carcinoma reverses Multidrug Resistance by SOCS1.

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MicroRNA-7 inhibits cell proliferation, migration and invasion in human non-small cell lung cancer cells by targeting FAK through ERK/MAPK signaling pathway

“…As more than 70% NSCLC patients are diagnosed with advanced-stage disease, it is urgent to investigate the molecular mechanism of NSCLC and new targeted therapy in the treatment of advanced NSCLC [5]. Currently, efforts to decipher signaling pathways provide new advances in the understanding of pathogenic mechanism of NSCLC, and microRNAs (miRs) differentially expressed in NSCLC may target molecular pathways involved in carcinogenesis [6–8]. …”

Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice

“…This may then allow constitutive activation of STATs in these cancers. We previously reported that overexpression of SOCS protein in cells using adenovirus vector was shown to have potent antiproliferative effects through targeting of the JAK/STAT signaling pathway and other signaling pathways . Because SOCS1 gene therapy targets multiple signaling pathways, it may be a promising therapeutic approach and could prevent the development of drug resistance in tumor cells …”