IL-6 controls resistance to radiation by suppressing oxidative stress via the Nrf2-antioxidant pathway in oral squamous cell carcinoma

Abstract

Background:In promoting tumour malignancy IL-6 signalling is considered to have an important role. However, the biological roles of IL-6 on radiosensitivity in oral squamous cell carcinoma (OSCC) remain largely unclear. The objective of this study is to determine the effects and molecular mechanisms of IL-6 on radiosensitivity in OSCC.Methods:Two OSCC cell lines, and OSCC tissue samples with radioresistant cells were used. We examined the effects of IL-6, or tocilizumab, a humanised anti-human IL-6 receptor antibody, or both on radiosensitivity and DNA damage after X-ray irradiation in vitro. In addition, we investigated the involvement of the Nrf2-antioxidant pathway in IL-6-mediated radioresistant mechanisms using OSCC cell lines and tissues.Results:Increased levels of IL-6 suppressed radiation-induced cell death, and the blockade of IL-6 signalling by tocilizumab sensitised tumour cells to radiation. The radioresistant effect of IL-6 was associated with decreased DNA damage after radiation. We also found that IL-6 promotes the activation of not only the downstream molecule STAT3 but also the Nrf2-antioxidant pathway, leading to a significant decrease in oxidative stress by upregulating Mn-SOD.Conclusions:These results indicate that the blockade of IL-6 signalling combined with conventional radiotherapy could augment the treatment response and survival rate in patients with radioresistant OSCC.

Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma

“…DSBs are more difficult to repair and are therefore more toxic and fatal to cancer cells [19]. To assess whether IGFBP-3 affects the number of DSBs in irradiated OSCC cells, we used γ-H2AX as a quantifiable marker after X-ray irradiation and identified cells with ≥ 10 γ-H2AX foci at 0.5 and 24 h after 10-Gy irradiation [20,21]. The frequency of γ-H2AX-positive SAS cells with IGFBP-3 knockdown (65.0 ± 7.8%) was higher than that in control cells (45.3% ± 7.2%) at 24 h ( Figure 3A,B).…”

“…HDS assays were performed as described by Kuwahara et al [21,40]. Exponentially growing cells (5 × 10 5 ) were seeded in 60-mm tissue culture dishes (AGG Inc., Tokyo, Japan) and incubated in DMEM supplemented with 10% FBS for 48 h. Cells were transfected with scrambled siRNA and then exposed to 2, 6, and 10 Gy.…”

Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic

“… 50 Although the clinical results thus far have been mixed, this approach continues to be studied in a variety of tumor types. 71 – 73 Meanwhile, the compounds OPB-31121 and OPB-51602 are being studied as STAT3 inhibitors, 74 , 75 but with some reservations. OPB-31121 downregulates JAK2 and the IL-6 receptor gp130, thereby decreasing STAT3 activation via upstream modulators.…”

MiRNAs in Radiotherapy Resistance of Nasopharyngeal Carcinoma

“…Moreover, the aforementioned NF-κB signaling pathway is also involved in the release and regulation of inflammatory molecules. In addition, IL-6 molecules have been reported to promote Stat3 and Nrf2-antioxidant pathway in oral squamous cell carcinoma, and up-regulation of Mn-SOD reduces oxidative stress leading to radiotherapy resistance [83]. However, more miRNAs and inflammatory factors play a role in radiotherapy resistance and specific pathways remain to be further explored.…”