Chemical Modulation of TRPM8 Ion Channels in Aggressive Brain Tumor Cells

Introduction: Glioblastoma (GBM), the most common and the deadliest primary brain cancer, has very poor prognosis. Currently new strategies are needed to tackle the challenges of treatment. Recent studies have suggested that glioblastoma, especially glioblastoma stem cells have striking resemblance to non-cancerous neural progenitor (NP) cells in terms of molecular mechanisms. Calcium signalling is found to be ubiquitously utilized both in GBM and NP cells. TRP channels – one of the calcium channels, play important role in normal functioning of NP cells as well as pathophysiology of GBM cells.

Aim: The aim of the present study is to assess levels of TRP channel expression in glioblastomas and neural progenitor cells, and to assess the changes in cell behaviour after inhibition of TRP channels using selective TRP channels inhibitors.

Methods: The present study examined the expression of TRP channels in glioblastoma using public database. This data is then validated in GBM and NP cell models by qRT-PCR. Changes in cellular behaviour and morphology after treatment with AMTB - TRP channels inhibitor are than assessed using live cell imaging and immunocytochemistry.

Results: The analysis of public database revealed that TRPV2, TRPV4, TRPC6 and TRPM8 channels are over expressed in glioblastomas compared to normal brain tissue. The results of qRT-PCR confirmed significantly higher expression of TRPM8 channels in glioblastoma compared to neural progenitor cells. Live cell imaging and immunocytochemistry showed that AMTB treatment resulted in severe toxicity and lead to cell death in glioblastomas, while some toxicity is revealed in NP cells without significant cell death.

Conclusion : TRPM8 channels levels are elevated in glioblastoma and appears to play an important role in glioblastoma aggressive behaviour. Pharmacological inhibition by a small molecule – AMTB hydrate causes cancer cell death in glioblastoma. Further studies are needed to validate TRPM8 as a target for developing novel therapeutic drugs.