Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
Mol Cancer Ther. 2019 Sep;18(9):1649-1658. doi: 10.1158/1535-7163.MCT-18-1251. Epub 2019 Jun 12.
Tenascin-C is a member of the matricellular protein family, and its expression level is correlated to poor prognosis in cancer, including glioblastoma, whereas its substantial role in tumor formation and malignant progression remains controversial. We reported previously that peptide TNIIIA2 derived from the cancer-associated alternative splicing domain of tenascin-C molecule has an ability to activate β1-integrin strongly and to maintain it for a long time. Here, we demonstrate that β1-integrin activation by TNIIIA2 causes acquisition of aggressive behavior, dysregulated proliferation, and migration, characteristic of glioblastoma cells. TNIIIA2 hyperstimulated the platelet-derived growth factor-dependent cell survival and proliferation in an anchorage-independent as well as -dependent manner in glioblastoma cells. TNIIIA2 also strongly promoted glioblastoma multiforme cell migration, which was accompanied by an epithelial-mesenchymal transition-like morphologic change on the fibronectin substrate. Notably, acquisition of these aggressive properties by TNIIIA2 in glioblastoma cells was abrogated by peptide FNIII14 that is capable of inducing inactivation in β1-integrin activation. Moreover, FNIII14 significantly inhibited tumor growth in a mouse xenograft glioblastoma model. More importantly, FNIII14 sensitized glioblastoma cells to temozolomide via downregulation of O-methylguanine-DNA methyltransferase expression. Consequently, FNIII14 augmented the antitumor activity of temozolomide in a mouse xenograft glioblastoma model. Taken altogether, the present study provides not only an interpretation for the critical role of tenascin-C/TNIIIA2 in aggressive behavior of glioblastoma cells, but also an important strategy for glioblastoma chemotherapy. Inhibition of the tenascin-C/β1-integrin axis may be a therapeutic target for glioblastoma, and peptide FNIII14 may represent a new approach for glioblastoma chemotherapy. SIGNIFICANCE: These findings provide a proposal of new strategy for glioblastoma chemotherapy based on integrin inactivation.
纤连蛋白连接蛋白 C 是细胞外基质蛋白家族的一员，其表达水平与包括神经胶质瘤在内的癌症预后不良相关，而其在肿瘤形成和恶性进展中的重要作用仍存在争议。我们之前报道过，源自纤连蛋白连接蛋白 C 分子癌相关可变剪接结构域的肽 TNIIIA2 具有强烈激活β1-整合素的能力，并能使其长时间保持激活状态。在这里，我们证明了 TNIIIA2 对β1-整合素的激活导致神经胶质瘤细胞获得侵袭性行为、失调增殖和迁移的特征。TNIIIA2 以依赖和不依赖锚定的方式，在血小板衍生生长因子依赖性细胞存活和增殖中强烈刺激神经胶质瘤细胞。TNIIIA2 还强烈促进多形性胶质母细胞瘤细胞迁移，这伴随着在纤维连接蛋白基质上上皮-间充质转化样形态变化。值得注意的是，在神经胶质瘤细胞中，FNIII14 肽能够诱导β1-整合素激活失活，从而阻止了 TNIIIA2 获得这些侵袭性特性。此外，FNIII14 显著抑制了小鼠异种移植神经胶质瘤模型中的肿瘤生长。更重要的是，FNIII14 通过下调 O-甲基鸟嘌呤-DNA 甲基转移酶表达使神经胶质瘤细胞对替莫唑胺敏感。因此，FNIII14 增强了替莫唑胺在小鼠异种移植神经胶质瘤模型中的抗肿瘤活性。总的来说，本研究不仅为 TNIIIA2 在神经胶质瘤细胞侵袭性行为中的关键作用提供了一种解释，也为神经胶质瘤化疗提供了一种重要策略。抑制纤连蛋白连接蛋白 C/β1-整合素轴可能成为神经胶质瘤的治疗靶点，FNIII14 肽可能代表神经胶质瘤化疗的新方法。意义：这些发现为基于整合素失活的神经胶质瘤化疗提供了一种新的策略。
