Members of the TRPM (“Melastatin”) family fall into the subclass of the TRP channels having varying permeability to Ca²⁺ and Mg²⁺, with three members of the TRPM family being chanzymes, which contain C-terminal enzyme domains. The role of different TRPM members has been shown in various cancers such as prostate cancer for mostly TRPM8 and TRPM2, breast cancer for mostly TRPM2 and TRPM7, and pancreatic cancer for TRPM2/7/8 channels. The role of TRPM5 channels has been shown in lung cancer, TRPM1 in melanoma, and TRPM4 channel in prostate cancer as well. Thus, the TRPM family of channels may represent an appealing target for the anticancer therapy.

It has been widely established that transient receptor potential vanilloid (TRPV) channels play a crucial role in calcium homeostasis in mammalian cells. Modulation of TRPV channels activity can modify their physiological function leading to some diseases and disorders like neurodegeneration, pain, cancer, skin disorders, etc. It should be noted that, despite TRPV channels importance, our knowledge of the TRPV channels functions in cells is mostly limited to their plasma membrane location. However, some TRPV channels were shown to be expressed in the endoplasmic reticulum where their modulation by activators and/or inhibitors was demonstrated to be crucial for intracellular signaling. In this review, we have intended to summarize the poorly studied roles and functions of these channels in the endoplasmic reticulum.

The TRPV6 calcium channel is known to be up-regulated in various tumors. The efforts to target the TRPV6 channel in vivo are still ongoing to propose an effective therapy against cancer. Here, we report the generation of two antibodies raised against extracellular epitopes corresponding to the extracellular loop between S1 and S2 (rb79) and the pore region (rb82). These antibodies generated a complex biphasic response with the transient activation of the TRPV6 channel. Store-operated calcium entry was consequently potentiated in the prostate cancer cell line LNCaP upon the treatment. Both rb79 and rb82 antibodies significantly decreased cell survival rate in a dose-dependent manner as compared to the control antibodies of the same isotype. This decrease was due to the enhanced cell death via apoptosis revealed using a sub-G1 peak in a cell cycle assay, TUNEL assay, and a Hoechst staining, having no effects in the PC3M^trpv6−/− cell line. Moreover, all TUNEL-positive cells had TRPV6 membrane staining as compared to the control antibody treatment where TRPV6-positive cells were all TUNEL negative. These data clearly demonstrate that TRPV6 channel targeting using rb79 and rb82 antibodies is fatal and may be successfully used in the anticancer therapies.

Cytosolic Ca²⁺ oscillations provide signaling input to several effector systems of the cell. These include neuronal development, migration and networking. Although similar signaling events are hijacked by highly aggressive cancer cells, the mechanism(s) driving the ′neuron-like′ remodeling of the intracellular ionic signature upon cancer progression remains largely elusive. Here, we identify the ′neuronal′ Na⁺ leak channel, NALCN, in metastatic cells at the hot spots of invadopodia formation and Ca²⁺ event initiation. Mechanistically, NALCN-mediated Na⁺ influx associates functionally with plasmalemmal and mitochondrial Na⁺/Ca²⁺ exchangers (NCX and NCLX), reactive oxygen species (ROS) and store-operated Ca²⁺ entry (SOCE)/endoplasmic reticulum ^Ca2+ uptake (SERCA) systems to generate intracellular Ca²⁺ oscillations. In turn, the oscillatory activity promotes Src-regulated actin remodeling, Ca²⁺-dependent secretion of proteolytic enzymes and leads to invadopodogenesis, resulting in tumor progression and metastatic lesions in vivo . Thus, we have uncovered malignant assignment of NALCN giving rise to a critical intracellular Na⁺/Ca²⁺ signaling axis.