Anoikis resistance conferred by tenascin-C-derived peptide TNIIIA2 and its disruption by integrin inactivation
Anoikis resistance conferred by tenascin-C-derived peptide TNIIIA2 and its disruption by integrin inactivation
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DOI：
10.1016/j.bbrc.2020.12.050
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发表时间：
2021-01-15
影响因子：
3.1
通讯作者：
Fukai, Fumio
中科院分区：
文献类型：
--
作者：
Fujita, Motomichi;Sasada, Manabu;Fukai, Fumio
多形性胶质母细胞瘤（GBM）是成人中最常见的脑肿瘤，具有极差的预后，这归因于GBM细胞的侵袭性，例如增殖失调和扩散性迁移。我们最近发现，肽TNIIIA 2，来自腱生蛋白-C（TNC），这是高度表达的GBM，有助于收购这些侵略性的特性，通过β 1-整联蛋白激活。一般来说，癌细胞通常获得额外的恶性性质，其由于与细胞外基质的粘附丧失而赋予对凋亡的抗性，称为失巢凋亡抗性。我们目前的研究结果表明，β 1-整合素激活的调节也发挥了关键作用的发展和GBM细胞失巢凋亡抵抗的损失。尽管衍生自预后极差的GBM，但人GBM细胞系T98 G对失巢凋亡敏感，但通过用能够激活β 1-整联蛋白的肽TNIIIA 2处理而变得抗失巢凋亡。通过进一步添加肽FNIIII 4（具有灭活β 1-整联蛋白的能力），T98 G细胞的TNIIIA 2赋予的失巢凋亡抗性被破坏。此外，悬浮培养物中GBM细胞的锚定非依赖性存活被肽FNIIII 4废除，但不被RGD和CS-1肽废除，其对整合素α 5 β 1、α v β 3和α 4 β 1具有拮抗作用。这些结果表明，GBM细胞通过TNC衍生肽TNIIIA 2激活β 1-整联蛋白产生抗失巢凋亡，TNIIIA 2大量释放到GBM的肿瘤微环境中。β 1-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有希望的策略。(C)2020爱思唯尔公司All rights reserved.
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 beta 1-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 beta 1-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 beta 1-integrin. The TNIIIA2-conferred anoikis resistance of T98G cells was disrupted by further addition of peptide FNIIII4, which has the ability to inactivate beta 1-integrin. Moreover, anchorage-independent survival of GBM cells in suspension culture was abrogated by peptide FNIIII4, but not by RGD and CS-1 peptides, which are antagonistic for integrins alpha 5 beta 1, alpha v beta 3, and alpha 4 beta 1. These results suggest that GBM cells develop anoikis resistance through activation of beta 1-integrin by TNC-derived peptide TNIIIA2, which is abundantly released into the tumor microenvironment of GBM. Inactivation of beta 1-integrin may provide a promising strategy to overcome the apoptosis resistance of cancer cells, including GBM. (C) 2020 Elsevier Inc. All rights reserved.