Yadav Arti, Kumar Bhavna, Teknos Theodoros N, Kumar Pawan
The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Department of Otolaryngology-Head and Neck Surgery, The Ohio State University, Columbus, OH 43210, USA.
Oncotarget. 2016 Aug 22;8(40):66912-66924. doi: 10.18632/oncotarget.11464. eCollection 2017 Sep 15.
Recent studies have shown that IL-6 signaling plays an important role in the aggressive and metastatic phenotype of head and neck squamous cell carcinoma (HNSCC). Therefore, we hypothesized that targeting of IL-6 signaling in HNSCC could enhance the therapeutic efficacy of standard chemoradiation treatment. We used both and models to test the efficacy of Bazedoxifene (BZA), a drug that was originally developed as a newer-generation selective estrogen receptor modulator (SERM) for the treatment of postmenopausal osteoporosis. Recently, BZA was also shown to exhibit potent anti-cancer effects that were both estrogen receptor (ER)-dependent and ER-independent. Our results suggest that BZA inhibits IL-6 signaling by disrupting IL-6R/gp130 protein-protein interactions. BZA treatment of CAL27-IL-6 (IL-6 overexpressing cells) or UM-SCC-74A (naturally expressing high levels of IL-6) significantly inhibited cell proliferation, migration and colony formation ability in a dose-dependent manner. In addition, BZA significantly decreased IL-6-mediated tumorsphere formation by markedly reducing nanog expression. BZA treatment also markedly reduced chemo and radioresistance in head and neck cancer cells by downregulating ERCC-1, XRCC-1 and survivin expression. In a SCID mouse xenograft model, BZA significantly enhanced the anti-tumor effects of cisplatin and radiation treatment with no added systemic toxicity. Furthermore, combination treatments significantly decreased tumor metastasis, pSTAT3 expression and nanog expression, . Taken together, our results suggest that targeting IL-6 signaling with bazedoxifene could be an effective treatment strategy for the treatment of HNSCC patients.
最近的研究表明，白细胞介素-6（IL-6）信号通路在头颈部鳞状细胞癌（HNSCC）的侵袭性和转移表型中起重要作用。因此，我们假设靶向HNSCC中的IL-6信号通路可以提高标准放化疗的治疗效果。我们使用了[具体模型1]和[具体模型2]模型来测试巴多昔芬（BZA）的疗效，BZA最初是作为一种新一代选择性雌激素受体调节剂（SERM）开发用于治疗绝经后骨质疏松症的药物。最近，BZA还被证明具有强大的抗癌作用，这些作用既依赖雌激素受体（ER）又不依赖ER。我们的结果表明，BZA通过破坏IL-6受体（IL-6R）/糖蛋白130（gp130）蛋白-蛋白相互作用来抑制IL-6信号通路。用BZA处理CAL27-IL-6（IL-6过表达细胞）或UM-SCC-74A（天然高水平表达IL-6的细胞）以剂量依赖性方式显著抑制细胞增殖、迁移和集落形成能力。此外，BZA通过显著降低nanog表达显著减少IL-6介导的肿瘤球形成。BZA处理还通过下调ERCC-1、XRCC-1和生存素表达显著降低头颈部癌细胞的化疗和放疗抗性。在严重联合免疫缺陷（SCID）小鼠异种移植模型中，BZA显著增强顺铂和放疗的抗肿瘤作用，且无额外的全身毒性。此外，联合治疗显著降低肿瘤转移、磷酸化信号转导和转录激活因子3（pSTAT3）表达和nanog表达。综上所述，我们的结果表明，用巴多昔芬靶向IL-6信号通路可能是治疗HNSCC患者的一种有效治疗策略。
