Recent Advances in Oncogenic Roles of the TRPM7 Chanzyme.

Transient Receptor Potential Melastatin-related 7 (TRPM7) is a non-selective cation channel fused with a functional kinase domain. Physiologically, TRPM7 channel is involved in magnesium homeostasis, cell survival and gastrulation. The channel part is responsible for calcium, magnesium, and metal trace entries. Cation current through TRPM7 channel is inhibited by both intracellular magnesium and magnesium complexed with nucleotides. In parallel, the kinase is able to phosphorylate cytoskeleton proteins like myosin chain regulating cell tension and motility. Moreover, TRPM7 kinase domain can be cleaved by caspase and participates to apoptosis signaling. Importantly, TRPM7 channel expression is aberrant in numerous cancers including breast, glioblastoma, nasopharynx, ovarian, and pancreatic. Moreover, TRPM7 high expression is an independent biomarker of poor outcome in breast cancer. Pharmacological modulation or silencing of TRPM7 strongly affects proliferation, adhesion, migration or invasion in cancer cell lines. Nevertheless, it is still not clear by which mechanism TRPM7 channels may disturb cancer cell hallmarks. In the present review, we will discuss the role of TRPM7 channels in malignancies. In particular, we will distinguish the role of cation signaling from kinase function in order to better understand how TRPM7 channels may play a central role in cancer progression. We will also discuss the recent advances in pharmacological blockers of TRPM7 and their potential use for cancer therapy.

Activation of P2RY11 and ATP release by lipoxin A4 restores the airway surface liquid layer and epithelial repair in cystic fibrosis.

In cystic fibrosis (CF), the airway surface liquid (ASL) height is reduced as a result of impaired ion transport, which favors bacterial colonization and inflammation of the airway and leads to progressive lung destruction. Lipoxin (LX)A4, which promotes resolution of inflammation, is inadequately produced in the airways of patients with CF. We previously demonstrated that LXA4 stimulates an ASL height increase and epithelial repair. Here we report the molecular mechanisms involved in these processes. We found that LXA4 (1 nM) induced an apical ATP release from non-CF (NuLi-1) and CF (CuFi-1) airway epithelial cell lines and CF primary cultures. The ATP release induced by LXA4 was completely inhibited by antagonists of the ALX/FPR2 receptor and Pannexin-1 channels. LXA4 induced an increase in intracellular cAMP and calcium, which were abolished by the selective inhibition of the P2RY11 purinoreceptor. Pannexin-1 and ATP hydrolysis inhibition and P2RY11 purinoreceptor knockdown all abolished the increase of ASL height induced by LXA4. Inhibition of the A2b adenosine receptor did not affect the ASL height increase induced by LXA4, whereas the PKA inhibitor partially inhibited this response. The stimulation of NuLi-1 and CuFi-1 cell proliferation, migration, and wound repair by LXA4 was inhibited by the antagonists of Pannexin-1 channel and P2RY11 purinoreceptor. Taken together, our results provide evidence for a novel role of LXA4 in stimulating apical ATP secretion via Pannexin-1 channels and P2RY11 purinoreceptors activation leading to an ASL height increase and epithelial repair.