TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets

Figure 4

A working model for the proliferative, prosurvival, and migratory roles of TRPM8 in pancreatic adenocarcinoma cells. The ion channel activity of TRPM8 can be stimulated by cold temperature, menthol, alkaline pH, or phosphatidylinositol-4,5-bis-phosphate (PIP₂), but inhibited by acidic pH. Once stimulated, the TRPM8 channel allows cellular influx of Ca²⁺, which in turn leads to activation of Ca²⁺-sensitive phospholipase C (PLC) and hydrolysis of PIP₂. These events provide negative feedback inhibition of the TRPM8 channel activity and also produce inositol-1,4,5-triphosphate (IP₃). As a consequence, Ca²⁺ is released from the intracellular stores and diacylglycerol (DAG) generated. The elevated Ca²⁺ or DAG activates protein kinase C (PKC) and thus RAF in the RAS/ERK pathway. These signaling events culminate in transcription of proliferative, prosurvival, and promigratory genes.