Recent Advances in Oncogenic Roles of the TRPM7 Chanzyme

Abstract

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.

Cadmium exposure enhances cell migration and invasion through modulated TRPM7 channel expression

“…Here, we show for the first time that TRPM7 channels participate in this neoplastic transformation. TRPM7 is a non-selective cation channel which is overexpressed in numerous cancers, including breast cancer and pancreatic ductal adenocarcinoma (Dhennin-Duthille et al 2011;Gautier et al 2016;Middelbeek et al 2012;Rybarczyk et al 2012;Yee et al 2015). We show that Cd 2+ exposure induces TRPM7 overexpression in both human mammary and pancreatic non-cancer epithelial cells, suggesting that TRPM7 could be used as a biomarker for cell transformation.…”

“…The low selectivity of TRPM7 towards divalent cations may also provide a favorite route for Cd 2+ in epithelial cell leading to cell transformation into a neoplastic phenotype. Numerous studies have shown that TRPM7 is involved in cancer progression (Gautier et al 2016). For instance, TRPM7 is overexpressed in breast cancer and this channel regulates MCF7 cell proliferation (Dhennin-Duthille et al 2011;Guilbert et al 2009).…”

Novel Channels of the Outer Membrane of Mitochondria: Recent Discoveries Change Our View

“…Interestingly, the mitochondrial enzyme succinate dehydrogenase has been proposed to be part of a complex giving rise to the mitochondrial ATP‐dependent potassium channel and some ion channels can function as enzyme (chanzymes) (e.g., Ref. ). To our knowledge this is the first case of a mitochondrial enzyme that is shown to function as an ion channel on its own.…”

Role of TRPM7 in Cancer: Potential as Molecular Biomarker and Therapeutic Target

“…Of the eight sub-families in the vertebral TRP family, the melastatin-subfamily (TRPM) possesses unique structural motifs and share common architectural features [4]. Growing evidence has shown that the TRPM7 member plays crucial roles in cellular processes, embryonic development, and human diseases, particularly cancer [5,6,7,8]. Accumulating data suggest the potential value of TRPM7 as a molecular biomarker and therapeutic target in human malignancies [5,8,9].…”