Tetraspanin 8-Rictor-Integrin α3 Complex Is Required for Glioma Cell Migration

Abstract

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in malignant gliomas. We found that Tspan8 expression level is high in both malignant glioma tissues and in several human glioma cell lines, where it formed a complex integrin α3 and rictor, the latter is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Disruption of this complex, through siRNA-mediated knockdown of anyone of these three proteins, inhibited U251MG glioma cell migration in vitro. We further showed that Tspan8-rictor association appeared required for mTORC2 activation. Knockdown of Tspan8 by the targeted siRNAs prevented mTOR-rictor (mTORC2) assembly as well as phosphorylation of AKT (Ser-473) and protein kinase C α (PKCα) in U251MG cells. Together, these results demonstrate that over-expressed Tspan8 in malignant glioma forms a complex with rictor and integrin α3 to mediate mTORC2 activation and glioma cell migration. Therefore, targeting Tspan8-rictor-integrin α3 complex may provide a potential therapeutic intervention for malignant glioma.

Tspan8 is expressed in breast cancer and regulates E‐cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles

“…These data are consistent with the hypothesis that the biological effects of tetraspanins are determined by their interacting partners . It seems that Tspan8 mediates cell motility via collaboration with integrins α6β4 in pancreatic cancer , α3β1 in gliomas , and α2β1 in colorectal cancer . Interaction with E‐cadherin resulted in a functional switch of Tspan8 in breast cancer.…”

“…Alongside increased cell–cell adhesion, Tspan8 supported cell–matrix adhesion to the BME. Since cell–cell and cell–matrix adhesion are functionally linked to each other and involved, alongside cadherins, also integrins , a connection between Tspan8 and integrins in breast cancer, as is already known from other cancer types , is possible. It may also explain the observed increase of proliferation in the 3D matrix in BME as a physiological response of the cells on signalling across the adhesive network .…”

Tetraspanin 8 is a novel regulator of ILK-driven β1 integrin adhesion and signaling in invasive melanoma cells

“…The fact that Tspan8 expression interfered only with Akt-S473 and not with Akt-T308 phosphorylation suggests that Tspan8 restricts full Akt activity in melanoma cells through inappropriate ILK activation, leading to attenuation of β1-integrin adhesive function. ILK interacts with Rictor to mediate Akt-S473 phosphorylation in different cell types [38] and Rictor may interact with Tspan8 in glioma cells [39]. Although the implication of Rictor in melanoma cells awaits further studies, we clearly demonstrate that in the absence of Tspan8, ILK-dependent Akt-S473 phosphorylation in response to ligation of β1 integrins occurs efficiently, leading to integrin clustering.…”

TSPAN8 as a Novel Emerging Therapeutic Target in Cancer for Monoclonal Antibody Therapy

“…The knockdown of TSPAN8 reduces proliferation and migration and increases the sensitivity of temozolomide (TMZ)-induced cell death and the apoptosis of glioma cells [79]. TSPAN8 forms a complex with Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR), a key component of mammalian target of rapamycin complex 2 (mTORC2), and integrin α3, which are required for mTORC2 activation and glioma cell migration [80]. Moreover, GSK621, a novel AMP-activated protein kinase (AMPK) activator, has shown anti-cancer activity in glioma cells by the degradation of TSPAN8 [81].…”