Role of Cl- channels in primary brain tumour

Abstract

There is tight interplay between Ca²⁺ and Cl^- flux that can influence brain tumour proliferation, migration and invasion. Glioma is the predominant malignant primary brain tumour, accounting for ˜80% of all cases. Voltage-gated Cl^- channel family (ClC) proteins and Cl^- intracellular channel (CLIC) proteins are drastically overexpressed in glioma, and are associated with enhanced cell proliferation, migration and invasion. Ca²⁺ also plays fundamental roles in the phenomenon. Ca²⁺-activated Cl^- channels (CaCC) such as TMEM16A and bestrophin-1 are involved in glioma formation and assist Ca²⁺ movement from intracellular stores to the plasma membrane. Additionally, the transient receptor protein (TRP) channel TRPC1 can induce activation of ClC-3 by increasing intracellular Ca²⁺concentrations and activating Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Therefore, Ca²⁺ and Cl^-currents can concurrently mediate brain tumour cellular functions. Glioma also expresses volume regulated anion channels (VRACs), which are responsible for the swelling-induced Cl^- current, I_Cl,swell. This current enables glioma cells to perform regulatory volume decrease (RVD) as a survivability mechanism in response to hypoxic conditions within the tumour microenvironment. RVD can also be exploited by glioma for invasion and migration. Effective treatment for glioma is challenging, which can be in part due to prolonged chemotherapy leading to mutations in genes associated with multi-drug resistances (MRP1, Bcl-2, and ABC family). Thus, a potential therapeutic strategy for treatment of glioma can be through the inhibition of selected Cl^- channels.

Keywords: Brain tumor; Calcium; Calcium signaling; Chloride channel; Glioma; Ion channels.