Abstract
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.
Highlights
Intracellular Ca2+ signals regulate a plethora of cellular functions, including exocytosis, proliferation, migration, differentiation, gene transcription, bioenergetics and survival [1,2]
Ruas and coworkers showed that NH2 -terminal truncated forms of TPC1 and TPC2 were expressed in the mouse line formerly presented as Two-pore channels (TPCs)-null and were able to rescue the Ca2+ response to nicotinic acid adenine dinucleotide phosphate (NAADP) in their truly knocked out TPCs model [129,141]
EL Ca2+ signalling through TRPML1-3 and two-pore channels 1-2 (TPC1-2) finely regulates cellular fate and behavior by driving the EL trafficking machinery and the autophagic flux, enabling the cells to adapt to stressful conditions, such as those imposed by lack of nutrients
Summary
Intracellular Ca2+ signals regulate a plethora of cellular functions, including exocytosis, proliferation, migration, differentiation, gene transcription, bioenergetics and survival [1,2]. An increase in intracellular Ca2+ concentration ([Ca2+ ]i ) is produced by the opening of Ca2+ -permeable channels, which are located either on the PM or on the membrane of endogenous organelles, in response to extracellular stimulation. The ER is by far the largest and best studied intracellular Ca2+ reservoir engaged by extracellular stimuli, possessing a complete repertoire of Ca2+ pumps, i.e., SERCA, to effect filling, luminal Ca2+ -binding proteins, e.g., calnexin and calreticulin, to effect buffering and Ca2+ -permeable channels, i.e., InsP3 Rs and RyRs, to effect release [7,12]. The establishment of EL-ER membrane contact sites (MCSs) enables EL Ca2+ release to trigger cytosolic Ca2+ waves by recruiting ER-resident InsP3 Rs and RyRs through the CICR process [17,18].
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