Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Clinical Research Center in Hiroshima, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan.
Biochem Biophys Res Commun. 2021 Jan 15;536:14-19. doi: 10.1016/j.bbrc.2020.12.050. Epub 2020 Dec 22.
Glioblastoma multiforme (GBM), the most common brain tumor in adults, has an extremely poor prognosis, which is attributed to the aggressive properties of GBM cells, such as dysregulated proliferation and disseminative migration. We recently found that peptide TNIIIA2, derived from tenascin-C (TNC), which is highly expressed in GBM, contributes to the acquisition of these aggressive properties through β1-integrin activation. In general, cancer cells often acquire an additional malignant property that confers resistance to apoptosis due to loss of adhesion to the extracellular matrix, termed anoikis resistance. Our present results show that regulation of β1-integrin activation also plays a key role in both the development and loss of anoikis resistance in GBM cells. Despite being derived from a GBM with an extremely poor prognosis, the human GBM cell line T98G was susceptible to anoikis but became anoikis resistant via treatment with peptide TNIIIA2, which is able to activate β1-integrin. The TNIIIA2-conferred anoikis resistance of T98G cells was disrupted by further addition of peptide FNIII14, which has the ability to inactivate β1-integrin. Moreover, anchorage-independent survival of GBM cells in suspension culture was abrogated by peptide FNIII14, but not by RGD and CS-1 peptides, which are antagonistic for integrins α5β1, αvβ3, and α4β1. These results suggest that GBM cells develop anoikis resistance through activation of β1-integrin by TNC-derived peptide TNIIIA2, which is abundantly released into the tumor microenvironment of GBM. Inactivation of β1-integrin may provide a promising strategy to overcome the apoptosis resistance of cancer cells, including GBM.
多形性胶质母细胞瘤（GBM）是成人中最常见的脑肿瘤，预后极差，这归因于 GBM 细胞的侵袭特性，如失调的增殖和扩散性迁移。我们最近发现，来源于腱生蛋白-C（TNC）的肽 TNIIIA2 高度表达于 GBM 中，通过激活β1-整合素有助于获得这些侵袭特性。一般来说，癌细胞由于丧失与细胞外基质的黏附而获得额外的恶性特性，从而对细胞凋亡产生抗性，称为失巢凋亡抗性。我们目前的结果表明，β1-整合素激活的调节在 GBM 细胞的失巢凋亡抗性的获得和丧失中也起着关键作用。尽管源自预后极差的 GBM，人 GBM 细胞系 T98G 易发生失巢凋亡，但通过用能够激活β1-整合素的肽 TNIIIA2 处理后变得具有失巢凋亡抗性。进一步添加具有使β1-整合素失活能力的肽 FNIII14 可破坏 TNIIIA2 赋予 T98G 细胞的失巢凋亡抗性。此外，在悬浮培养中，肽 FNIII14 可破坏 GBM 细胞的无锚定生存能力，但肽 RGD 和 CS-1 不能，它们分别是整合素 α5β1、αvβ3 和 α4β1 的拮抗剂。这些结果表明，GBM 细胞通过 TNC 衍生的肽 TNIIIA2 激活β1-整合素而获得失巢凋亡抗性，该肽大量释放到 GBM 的肿瘤微环境中。β1-整合素的失活可能为克服包括 GBM 在内的癌细胞的凋亡抗性提供一个有前途的策略。
