Abstract 1348: Suppressor of cytokine signaling (SOCS)-1 suppresses a proliferation of malignant melanoma cells via the suppression of JAK/STAT and the activation of p53 signaling pathways
Authors: Tagami Naoko , Serada Satoshi , Fujimoto Minoru , Tanemura Atsushi , Katayama Ichiro , Naka Tetsuji 
Published: May 2015

Abstract
BACKGROUND : Melanoma is the most aggressive form of skin cancer, responsible for the majority of skin cancer related deaths. JAK-STAT signal is one of the main pathways involved in the tumor growth in melanoma, because JAK inhibitor has been reported to induce apoptosis in melanoma cells. The suppressor of cytokine signaling (SOCS) family proteins are important negative regulator of proinflammatory cytokine signals by suppressing JAK-STAT signal pathway via inhibiting JAK activity. The aim of this study was to evaluate the role of SOCS-1 in the proliferation of melanoma through regulating cytokine signaling pathway and to clarify the mechanisms of its antitumor effect in vitro and in vivo. MATERIAL AND METHODS : Adenovirus vectors encoding SOCS1 gene was used to overexpress SOCS1 in three melanoma cell lines (G361, SK-MEL5, and SK-MEL28). The status of activated kinases and downstream proteins were determined by Western blot analysis. Anti-proliferative effects in melanoma cells were assessed by MTT assay. Apoptosis in melanoma cells was assessed by Caspase 3 activity and TUNEL staining. ICR nu/nu mice were used for subcutaneous xenograft experiment. RESULTS : High levels of phosphorylated STAT3 in G361 and SK-MEL5, but not in SK-MEL28. Overexpression of SOCS1 significantly reduced cell proliferation and induced apoptosis in G361 and SK-MEL5. Furthermore, in G361 and SK-MEL5 xenograft model, intratumoral injection of AdSOCS1 vector significantly reduced tumor volumes compared to AdLacZ-injected mice. Western blot and immunohistochemical analysis indicated that SOCS1 was overexpressed and induced apoptosis in the tissues from AdSOCS1-injected mice. The anti-proliferative effect of SOCS1 correlated with decreased levels of the activation of STAT3 and increased levels of p53. Furthermore the G0/G1 cell population was increased by overexpression of SOCS1 in G361. On the other hand, in SK-MEL28, SOCS1 delivery didn't reduce cell proliferation so markedly. CONCLUSIONS : We showed that overexpression of SOCS-1 suppresses a proliferation of G361 and SK-MEL5 malignant melanoma cells via the suppression of JAK/STAT and the activation of p53 signaling pathways. Overexpression of SOCS-1 resulted in the cell cycle arrest at G1/S phase. Furthermore, we firstly demonstrated that overexpression of SOCS-1 induced apoptosis in melanoma cells in vitro and in vivo. Therefore, low levels of phosphorylated STAT3 as well as a mutation of p53 in SK-MEL28 may be the reason why SOCS1 didn't reduce cell proliferation so markedly in SK-MEL28. We hope that these findings may lead to the successful clinical application of SOCS1 for melanoma treatment.
Citation Format: Naoko Tagami, Satoshi Serada, Minoru Fujimoto, Atsushi Tanemura, Ichiro Katayama, Tetsuji Naka. Suppressor of cytokine signaling (SOCS)-1 suppresses a proliferation of malignant melanoma cells via the suppression of JAK/STAT and the activation of p53 signaling pathways. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1348. doi:10.1158/1538-7445.AM2014-1348