Receptor Channel TRPC6 Is a Key Mediator of Notch-Driven Glioblastoma Growth and Invasiveness

Abstract

Glioblastoma multiforme (GBM) is the most frequent and incurable type of brain tumor of adults. Hypoxia has been shown to direct GBM toward a more aggressive and malignant state. Here we show that hypoxia increases Notch1 activation, which in turn induces the expression of transient receptor potential 6 (TRPC6) in primary samples and cell lines derived from GBM. TRPC6 is required for the development of the aggressive phenotype because knockdown of TRPC6 expression inhibits glioma growth, invasion, and angiogenesis. Functionally, TRPC6 causes a sustained elevation of intracellular calcium that is coupled to the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Pharmacologic inhibition of the calcineurin-NFAT pathway substantially reduces the development of the malignant GBM phenotypes under hypoxia. Clinically, expression of TRPC6 was elevated in GBM specimens in comparison with normal tissues. Collectively, our studies indicate that TRPC6 is a key mediator of tumor growth of GBM in vitro and in vivo and that TRPC6 may be a promising therapeutic target in the treatment of human GBM.

Ionic Channels in the Therapy of Malignant Glioma

“…Hypoxia treatment (CoCl 2 treatment) could activate TRPC6 channels and boost the ability of glioma proliferation and invasion. Inhibition of TRPC6 channels reversed the hypoxia-induced proliferation and invasion (Chigurupati et al, 2010). It is known that Notch signaling pathway is important for development and for maintaining cells in an undifferentiated state by regulating the transcription of many critical proteins (Artavanis-Tsakonas et al, 1999), these results suggest that Notch-induced TRPC6 expression may enhance undifferentiated state of glioma cells and therefore enhance the aggressiveness of glioma cells.…”

“…TRPC channels regulate neuronal survival, neurite development, synapse formation, axon guidance, endothelial permeability, cell migration, differentiation and proliferation (Ahmmed & Malik, 2005;Cai et al, 2006;Florio Pla et al, 2005;Jia et al, 2007;Li et al, 2005;Louis et al, 2008;Tai et al, 2008;Zhou et al, 2008;). Among the seven TRPC members, TRPC1 and TRPC6 have been reported to play important roles in glioma cell proliferation, migration and invasion, TRPC6 channels are also involved in tumor angiogenesis Chigurupati et al, 2010;Ding et al, 2010;Ge et al, 2009;Hamdollah Zadeh et al, 2008 Table 2. Schematic topology of subunit and subunit assembly of glioma-related ion channels.…”

Functional properties of ion channels and transporters in tumour vascularization

“…In this context, the recent interest in human 'transportome' involvement in tumour vascularization is a promising field, because several members are activated downstream of the recruitment of VEGF receptors. For example, whereas the interference with the bulk VEGF signalling alters the activity of a multitude of different cells and functions, targeting TRPC6 or Orai1 may affect only EC migration and proliferation [31,34,44,53,92], whereas TRPC1 and STIM1 may selectively influence vascular permeability [56][57][58]61].…”

“…For example, TRPC6 channels targeting could affect VEGF release from tumour cells as well as EC migration and tumour vascularization [31,44,53].…”

“…TRPC6 can also exert its proangiogenic role indirectly through its activity on cancer cells. In glioma cells from glioblastoma multiforme, inhibition of hypoxia enhanced TRPC6 expression and NFAT activation, markedly reducing the number of branch points in EC grown in conditioned medium harvested from glioma cells [53] (table 1 and figure 2).…”