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.