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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Chigurupati S,Venkataraman R,Barrera D,Naganathan A,Madan M,Paul L,Pattisapu JV,Kyriazis GA,Sugaya K,Bushnev S,Lathia JD,Rich JN,Chan SLdoi
10.1158/0008-5472.CAN-09-2654subject
Has Abstractpub_date
2010-01-01 00:00:00pages
418-27issue
1eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-09-2654journal_volume
70pub_type
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