Suppression of SOCS3 increases susceptibility of renal cell carcinoma to interferon‐α

Abstract

Interferon (IFN)-a is one of the most commonly used agents in immunotherapy for patients with advanced stage renal cell carcinoma. However, because of the drug resistance to IFN-a, its benefits are limited. In this study, we examined whether repression of suppressor of cytokine signaling (SOCS) proteins, which are involved in the IFN-induced signaling pathway, can overcome the IFN resistance of renal cell carcinoma. The effect of IFN-a on SOCS3 expression and cell proliferation was examined using IFN-resistant 786-O and IFN-sensitive ACHN cell lines. The effects of SOCS3-targeted siRNA on 786-O xenografts were determined by SOCS3 expression, morphological observation, and tumor volume. The Although over half of renal cancers are found incidentally due to improved radiological evaluation, a quarter of the patients present with advanced disease, including locally advanced or metastatic RCC.As a therapeutic strategy against RCC, surgery is the standard treatment for localized disease. However, its role in the presence of distant metastases is limited. Furthermore, the role of radiotherapy is also limited to palliation of symptoms, and hormonal treatment and chemotherapy are ineffective. Recently, novel targeted agents have been used for the treatment of advanced RCC.(2,3) Randomized phase III trials of the targeted agents versus interferon (IFN) in patients with metastatic RCC have shown benefits associated with the use of these targeted agents. (2,4,5) In the era of molecular targeted agents, immunotherapy seems to have a minimal role in the management of advanced RCC. However, the combination of immunotherapy with molecular targeted agents is of great interest as a potential first-line therapy. Moreover, IFN-a is still one of the options as a subsequent therapy for progressive disease in the National Comprehensive Cancer Network practice guidelines (http://www.nccn.org/ index.asp). It is possible that improving the sensitivity of RCC against IFN-a would contribute to an improvement in the therapeutic effect against advanced RCC.Interferon-a is one of the most frequently used agents in immunotherapy against metastatic or recurrent RCC. Many reports have indicated that IFN-a therapy improved the survival of RCC patients.(6,7) Although this agent can lead to a complete response, (6,7) and can be used as an alternative in non-responders to targeted therapy, its benefits are limited due to drug resistance. Interferon-a can exert a direct antiproliferative response by modulating the expression of proteins that control cell cycle entry and exit, and cell cycle progression, and can also mediate apoptosis by regulating tumor necrosis factor-induced signaling events.(8) Among the IFN-a signalings, the Janus kinase ⁄ signal transducer and activator of transcription (JAK ⁄ STAT) pathway is one of the most important signal transduction cascades. In this pathway, the suppressor of cytokine signaling (SOCS) protein family is known to act as negative regulators of IFN-a signaling by inhibiting the JAK ⁄ STAT pathway.(9) Eight SO...

Interleukin-6 as an emerging regulator of renal cell cancer

“…Administration of tocilizumab, a humanized recombinant monoclonal antibody against the human soluble and membrane-bound cellular receptors of IL-6, with IFN-α to mice, retards tumor growth in comparison with controls: mice treated only with tocilizumab, mice treated only with IFN-α, and mice that were not treated [97]. Moreover, targeting IL-6R with tocilizumab inhibits both phosphorylation of STAT3 and SOCS3 expression, which is a key component in RCC resistance to IFN-α treatment [97,98]. The authors suggest that inhibition of IL-6 signaling alone is insufficient without IFN-α stimulation, and therapeutic approaches should be designed in a way to treat patients with RCC with more than 1 drug [97].…”

The Role of Inflammation in Kidney Cancer

“…IL-6 causes upregulation of the suppressor of cytokine signaling-3 (SOCS3) which plays a role in IFN-α resistance in RCC by inactivating cytokine-induced janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway (Tomita et al 2011). IFN-α stimulation induced IL-6 secretion and both IL-6 and SOCS3 mRNA expression in RCC cell lines.…”

Suppressors of Cytokine Signaling Inhibit Tubular Epithelial Cell-Myofibroblast Transdifferentiation

“…Moreover, SOCS-1 and SOCS-3 could abrogate renal damage, which is concerned with the suppression of JAK/STAT pathway [20,21]. Additionally, in vitro research has shown that overexpression of SOCS-1 and SOCS-3 can inhibit p-JAK2, p-STAT1 and p-STAT3 expression [22,23] and that SOCS-3 downregulation in 786-O cell lines by SOCS-3-targeted siRNA can increase the phosphorylation level of STAT1 rather than STAT3 [24]. Thus, we have reason to speculate that SOCS-1 and SOCS-3 can inhibit TEMT induced by IL-1β and OSM.…”