Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.
Mol Cancer Ther. 2010 Nov;9(11):2960-9. doi: 10.1158/1535-7163.MCT-10-0489. Epub 2010 Sep 21.
The mammalian target of rapamycin (mTOR) is engaged in the molecular pathogenesis of oral squamous cell carcinoma, which frequently invades the maxilla or the mandible. However, the effects of a mTOR inhibitor on bone destruction associated with oral squamous cell carcinoma are still unclear. In this study, we investigated the antitumor effect of temsirolimus-mediated mTOR inhibition against advanced oral squamous cell carcinoma. Temsirolimus inhibited the proliferation and migration of HSC-2 oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. Significantly, we clearly show that temsirolimus inhibited osteoclast formation both in vitro and in vivo. Reverse transcriptase-PCR analysis showed that temsirolimus decreased the mRNA expression of receptor activator for nuclear factor-κB ligand, known as an osteoclast differentiation factor in bone stromal ST2 cells. Moreover, temsirolimus normalized blood-free calcium concentration in mouse models for humoral hypercalcemia. These findings suggest that mTOR signaling is a potential target of oral squamous cell carcinoma associated with bone destruction, and hence we describe the efficacy of temsirolimus for the treatment of advanced oral squamous carcinoma.
哺乳动物雷帕霉素靶蛋白（mTOR）参与口腔鳞状细胞癌的分子发病机制，口腔鳞状细胞癌常侵犯上颌骨或下颌骨。然而，mTOR 抑制剂对与口腔鳞状细胞癌相关的骨破坏的影响尚不清楚。在这项研究中，我们研究了雷帕霉素介导的 mTOR 抑制对晚期口腔鳞状细胞癌的抗肿瘤作用。雷帕霉素在体外抑制 HSC-2 口腔鳞状细胞癌细胞的增殖和迁移，并抑制口腔鳞状细胞癌异种移植物在体内的生长。重要的是，我们清楚地表明，雷帕霉素在体外和体内均抑制破骨细胞的形成。逆转录-PCR 分析显示，雷帕霉素降低了核因子-κB 配体受体激活剂的 mRNA 表达，核因子-κB 配体是骨基质 ST2 细胞中的破骨细胞分化因子。此外，雷帕霉素使体液性高钙血症的小鼠模型中的游离钙浓度正常化。这些发现表明 mTOR 信号是与骨破坏相关的口腔鳞状细胞癌的潜在靶点，因此我们描述了雷帕霉素治疗晚期口腔鳞状癌的疗效。
