Endolysosomal Ca²⁺ Signalling and Cancer Hallmarks: Two-Pore Channels on the Move, TRPML1 Lags Behind!

The acidic vesicles of the endolysosomal (EL) system are emerging as an intracellular Ca²⁺ store implicated in the regulation of multiple cellular functions. The EL Ca²⁺ store releases Ca²⁺ through a variety of Ca²⁺-permeable channels, including Transient Receptor Potential (TRP) Mucolipin 1-3 (TRPML1-3) and two-pore channels 1-2 (TPC1-2), whereas EL Ca²⁺ refilling is sustained by the proton gradient across the EL membrane and/or by the endoplasmic reticulum (ER). EL Ca²⁺ signals may be either spatially restricted to control vesicle trafficking, autophagy and membrane repair or may be amplified into a global Ca²⁺ signal through the Ca²⁺-dependent recruitment of ER-embedded channels. Emerging evidence suggested that nicotinic acid adenine dinucleotide phosphate (NAADP)-gated TPCs sustain multiple cancer hallmarks, such as migration, invasiveness and angiogenesis. Herein, we first survey the EL Ca²⁺ refilling and release mechanisms and then focus on the oncogenic role of EL Ca²⁺ signaling. While the evidence in favor of TRPML1 involvement in neoplastic transformation is yet to be clearly provided, TPCs are emerging as an alternative target for anticancer therapies.