Abstract
Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation and motility. They are expressed by glioma cells and may contribute to their malignant phenotype. Integrin inhibition may therefore represent a promising therapeutic strategy. GL-261 and SMA-560 glioma cells grown under standard conditions uniformly detached and formed large cell clusters after integrin gene silencing or pharmacological inhibition using EMD-121974, a synthetic Arg-Gly-Asp-motif peptide, or GLPG0187, a nonpeptidic integrin inhibitor. After 120 h, the clusters induced by integrin inhibition decayed and cells died. In contrast, when cells were cultured under stem cell (sphere) conditions, no disaggregation became apparent upon integrin inhibition, and cell death was not observed. As poly-HEMA-mediated detachment had similar effects on cell viability as integrin inhibition, we postulated that cell death may result from detachment alone, which was confirmed using various permissive and nonpermissive substrates. No surrogate markers of apoptosis were detected and electron microscopy confirmed that necrosis represents the dominant morphology of detachment-induced cell death. In addition, integrin inhibition resulted in the induction of autophagy that represents a survival signal. When integrins were inhibited in nonsphere glioma cells, the TGF-β pathway was strongly impaired, whereas no such effect was observed in glioma cells cultured under sphere conditions. Cell death induced by integrin inhibition was rescued by the addition of recombinant transforming growth factor-β (TGF-β) and accelerated by exposure to the TGF-β receptor inhibitor, SD-208. In summary, cell death following integrin inhibition is detachment mediated, represents an atypical form of anoikis involving necrosis as well as autophagy, and is modulated by TGF-β pathway activity.
Highlights
Integrins are a family of heterodimeric cell surface receptors formed by a combination of 18 a-subunits and 8 b-subunits.[1]
Adherent cells grown under standard conditions, referred to as nonsphere (NS) cells, detached after exposure to the integrin inhibitor cilengitide (Cil, EMD121974), but not after exposure to the control peptide RAD
We explored whether integrin inhibition interferes with transforming growth factor-b (TGF-b) signaling in mouse glioma cells.[15]
Summary
Integrins are a family of heterodimeric cell surface receptors formed by a combination of 18 a-subunits and 8 b-subunits.[1]. Integrin interactions, signals are transduced into the cell through the activation of integrin-associated proteins and the establishment of focal adhesions.[3,4] Ligated integrins can activate prosurvival pathways by several mechanisms such as the induction of the phosphatidylinositol 3-kinase (PI3K)/. AKT,[5] NF-kB6 and RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathways,[7] as well as the induction of BCL-28 and FADD-like IL-1b-converting enzyme (FLICE)inhibitory protein (FLIP) expression,[9] and reduction of p53 activity.[10] In contrast, unligated integrins expressed on adherent cells or the antagonism of avb[3] or b1 integrins can induce apoptosis.[3,11] Loss of ECM contact of adherent cells by disruption of integrin ligation promotes death by anoikis, and this form of cell death can be prevented by integrinmediated adhesion.[10,11,12] Anoikis is deregulated in various pathological conditions and anchorage-independent growth is a hallmark of tumorigenic transformation of cells favoring metastasis.[10,13]. TGF-b is a multipotent cytokine with important effects on glioma cell proliferation, angiogenesis, invasion and immunity.[16,17] Integrins have been attributed an important role in the activation of TGF-b
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