Simple Summary

Autophagy is a cellular self-eating process that uses lysosome, the waste disposal system of the cell, to degrade and recycle intracellular materials to maintain cellular homeostasis. Defects in autophagy are linked to a variety of pathological states, including cancer. Calcium is an important cellular messenger that regulates the survival of all animal cells. Alterations to calcium homoeostasis are associated with cancer. While it has long been considered as cellular recycling center, the lysosome is now widely known as an intracellular calcium store that regulates autophagy and cancer progression by releasing calcium via some ion channels residing in the lysosomal membrane. In this review, we summarize existing mechanisms of autophagy regulation by lysosomal calcium channels and their implications in cancer development. We hope to guide readers toward a more in-depth understanding of the importance of lysosomal calcium channels in cancer, and potentially facilitate the development of new therapeutics for some cancers.

Abstract

Ca²⁺ is pivotal intracellular messenger that coordinates multiple cell functions such as fertilization, growth, differentiation, and viability. Intracellular Ca²⁺ signaling is regulated by both extracellular Ca²⁺ entry and Ca²⁺ release from intracellular stores. Apart from working as the cellular recycling center, the lysosome has been increasingly recognized as a significant intracellular Ca²⁺ store that provides Ca²⁺ to regulate many cellular processes. The lysosome also talks to other organelles by releasing and taking up Ca²⁺. In lysosomal Ca²⁺-dependent processes, autophagy is particularly important, because it has been implicated in many human diseases including cancer. This review will discuss the major components of lysosomal Ca²⁺ stores and their roles in autophagy and human cancer progression.

Keywords: lysosome, ion channel, calcium, autophagy, cancer

2.1. Lysosomal Ca²⁺ Release

Lysosomal Ca²⁺ is mainly released through TRPML1, which belongs to the TRPML channel family including TRPML1, TRPML2, and TRPML3. TRPML proteins form tetramers, and each pore-forming subunit contains six transmembrane domains (TM1–TM6 or S1–S6) (Figure 2A–C). While TRPML1 is predominantly localized on the late endosomes and the lysosomes, TRPML2 and TRPML3 are primarily on the recycling endosomes and the early endosomes, respectively. In contrast to TRPML1, which is ubiquitously expressed in all tissues, TRPML2 and TRPML3 expressed in specific organs [42].

TRPML1 is a Ca²⁺-permeable, non-selective cation channel that can be activated by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] [43,44] but inhibited by mTORC1 [22,45]. Normally under nutrient rich conditions, mTORC1 phosphorylates and inhibits TRPML1. During starvation, a reduction in mTORC1 activates TRPML1, stimulating the TFEB-dependent autophagy pathway, helping the cell survive extreme conditions [22]. TRPML1 is also regulated by some compounds, including mucolipin-specific synthetic agonists (ML-SAs) [46,47] and synthetic inhibitors ML-SIs [45] (Table 1). Physiologically, TRPML1 plays an important role in membrane trafficking, autophagy, lysosomal biogenesis, and lysosomal exocytosis [42,48]. Deficient TRPML1 causes type IV mucolipidosis (ML-IV), an autosomal recessive lysosomal storage disorder showing psychomotor retardation. Impaired TRPML1 has also been implicated in several other LSDs [49].

Two-pore channels, including TPC1 and TPC2 in human, are widely expressed in the endolysosomal system. They form a homodimer, with each pore-forming subunit comprising two repeats of six-transmembrane domains (Figure 2D,E). Functional TPC1/2 are dimetric non-selective Na⁺/Ca²⁺ channels that can be evoked by both NAADP and PI(3,5)P2 [43,57,62,63,64]. While TPC1 is expressed in both the early endosomes and the lysosomes, TPC2 is predominantly present on the lysosomal membranes [65]. TPCs are normally suppressed by intracellular ATP through mTORC1 kinase. Starvation and pharmacological inhibition of mTORC1 leads to TPC-dependent Ca²⁺ release to regulate autophagy [65,66] (Figure 3). Pharmacologically, both TPC1 and TPC2 are activated by a group of antidepressants LyNa-VAs and LyNA (i.e., Riluzole) [57]. TPC2 is also activated by two lipophilic and structurally distinct compounds TPC2-A1-N and TPC2-A1-P [61]. On the other hand, a structural analog of NAADP Ned 19 [60] and a bis-benzylisoquinoline alkaloid Tetrandrine [58,59] have been suggested to inhibit both TPC1 and TPC2, although definitive evidence supporting this claim is still lacking (Table 1).

P2X4 is a trimeric 2 helix-transmembrane channel that belongs to the ionotropic P2X-family ATP receptors. P2X4 is gated by intraluminal ATP to mediate Ca²⁺ release from the lysosome. P2X4 activity is also regulated by lysosomal pH with acidic luminal pH suppressing its activity [67,68]. Activation of P2X4-dependent Ca²⁺ release has been reported to promote lysosome fusion in a CaM-dependent manner [38].

Several other Ca²⁺ channels have been suggested to be expressed in the lysosome as well. These include transient receptor potential ankyrin 1 (TRPA1), a Ca²⁺-permeable non-selective cation channel found in somatosensory neurons [69]; transient receptor potential melastatin 2 (TRPM2), a Ca²⁺ permeable non-selective cation channel gated by ADP-ribose and Ca²⁺ [70]; snd P/Q-type voltage gated Ca²⁺ channels (VGCCs), Ca²⁺ channels regulating the fusion of autophagosomes with lysosomes in neurons [64]. However, their functions in lysosomes have not been determined by direct lysosome-patch-clamp recording. Currently, the major Ca²⁺ channels involved in the autophagy are TRPMLs and TPCs channels.

2.2. Lysosomal Ca²⁺ Store Refilling

Due to the storage capacity, the lysosome needs to be refilled with Ca²⁺ after release. The refilling of lysosomal Ca²⁺ store seems to be dependent on the lysosomal H⁺ (Figure 1), because (1) elevation of lysosomal pH and inhibition of V-ATPase deplete Ca²⁺ store [33,36,46]; (2) Ca²⁺ store is maintained through the Ca²⁺-H⁺ exchanger (CAX) in the vacuoles of yeast and plant, which is from some respects the equivalent of lysosomes in animal cells [36]. Therefore, it is conceivable that Ca²⁺/H⁺ exchanger may take part in the Ca²⁺ uptake in the lysosome [33,36]. However, in addition to triggering lysosomal Ca²⁺ release, manipulation of lysosomal pH may affect lysosomal Ca²⁺ concentration or its measurement. For example, because the lysosome contains substantial Ca²⁺ buffers [71] that binds Ca²⁺ much better at neutral pH [72], increasing lysosomal pH may reduce lysosomal free Ca²⁺ without necessarily triggering lysosomal Ca²⁺ release and affecting total Ca²⁺ content [72]. Lysosomal pH may also affect the chromophore fluorescence and Ca²⁺-binding affinity (K_d) of Ca²⁺ dyes sequestered in the lumen, becauseK_d drops significantly when lysosomal pH increases [71]. Additionally, lysosomal pH elevation may indirectly affect lysosomal Ca²⁺ homeostasis by regulating membrane fusion and fission between compartments containing different amounts of Ca²⁺, H⁺, and their buffers [36,73]. To study lysosomal Ca²⁺ refilling under more physiological conditions, Garrity et al. [73] have adopted a lysosome-targeted GCaMP (fused to the cytosolic N-terminus of TRPML1) [46] to directly monitor the real-time changes in lysosomal Ca²⁺. They reported that inhibition of the H⁺ gradient in the lysosome, for example, by V-ATPase inhibitors, did not affect Ca²⁺ refilling. Therefore, the identity of the channel or exchanger mediating lysosomal Ca²⁺ uptake is still unclear [33,36]. In line with this, it has been previously suggested that Ca²⁺ uptake into lysosomes is mediated by a low-affinity Ca²⁺ transporter [74]. Very recently, the P5 ATPase ATP13A2 was suggested to mediate lysosomal Ca²⁺ entry [37]. However, whether ATP13A2 transport Ca²⁺ into lysosomes is regulated by H⁺ gradient across the lysosomal membrane remains unclear.

ER Ca²⁺ has been suggested to play an important role in Ca²⁺ refilling [73]. Moreover, it is IP3 receptors (IP3Rs) rather than ryanodine receptors (RyRs) that are involved in this process. Thus, a three step model has been proposed based on the structurally intimate localization of the ER and the lysosome [75,76]: (1) refilling stimulated by increased peri-lysosomal Ca²⁺ and/or decreased lysosomal Ca²⁺; (2) formation of ER-lysosome membrane contact sites (MCS) [73,77,78,79]; and (3) Ca²⁺ transport from the ER to the lysosome through functional ER–lysosome membrane contact sites.

2.3. Crosstalk between Lysosomes and Other Ca²⁺ Stores

By releasing and taking up Ca²⁺, the lysosomes, along with the ER, modulate cytosolic Ca²⁺ signaling events. On the one hand, lysosomal Ca²⁺ release can induce Ca²⁺ release from the ER using a mechanism similar to the Ca²⁺ induced Ca²⁺ release (CICR). This further causes Ca²⁺ entry from the extracellular space due to the depletion of the ER Ca²⁺ store, evoking global Ca²⁺ signals in human cells [80]. Both TRPML1 [81] and TPC2 [82,83,84]-mediated Ca²⁺ release are involved in this process. On the other hand, increasing evidence has suggested that, when lysosomal Ca²⁺ store is depleted, Ca²⁺ in the ER is transported to the lysosome via IP3R to refill the lysosome with Ca²⁺ [73,85]. The bidirectional Ca²⁺ signaling between the lysosome and the ER [86] has also been supported by the identification of the ER–lysosome contact sites [77,87] (Figure 4). In addition, new evidence suggests that the lysosome may also act as a Ca²⁺ buffer to shape extracellular Ca²⁺ entry and the ER Ca²⁺ re-uptake [85].

Interorganellular contacts between mitochondria and lysosomes have also been suggested recently [88,89,90]. Using high-resolution microscopy, Wong et al. [88,89] identified a dynamic formation of contact sites between mitochondria and lysosomes that were regulated by Rab7, a small GTPase associated with lysosomes. These contact sites allow bidirectional crosstalk between mitochondria and lysosomes and regulate the organelle network dynamics, such as mitochondrial fission. By high spatial and temporal resolution live-cell microscopy, they further suggested a role of the mitochondria–lysosome contact in regulating mitochondrial Ca²⁺ dynamics by lysosomal TRPML1, i.e., in the presence of mitochondria–lysosome contact, lysosomal Ca²⁺ release through TRPML1 promotes Ca²⁺ transfer to mitochondria [90] (Figure 4). Taken together, emerging evidence suggests that the lysosome may regulate intracellular Ca²⁺ signaling by buffering ER Ca²⁺ release and uptake, mitochondrial Ca²⁺ release uptake, and extracellular Ca²⁺ influx.

4.1. TRPML Channels in Autophagy

It is widely accepted that Ca²⁺ can regulate autophagy, while mechanisms differ depending on the conditions. The interplay between lysosomal Ca²⁺ signal and autophagy has also been reported. In line with this, several lysosomal Ca²⁺-permeable channels have been suggested to regulate autophagy [119,120,121].

As a key Ca²⁺ release channel in the lysosomal membrane, TRPML1 deficiency leads to defective autophagy including accumulation of autophagosomes and aggregation of p62 proteins [122,123,124,125]. Growing evidence suggests that TRPML1 plays multifaceted roles in autophagy. Under normal conditions, mTORC1 phosphorylates and inhibits both TRPML1 and TFEB. Cellular stress activates TRPML1 due to mTORC1 inhibition. This further activates downstream pathways including (1) CaM/CaMKKβ/AMPK-dependent autophagosome formation [126], (2) ALG-2-dependent lysosome centripetal movement to promote autophagosome–lysosome fusion [45], (3) proteolytic degradation in autolysosomes [127], (4) Syt7-dependent lysosomal exocytosis to remove cellular garbage [45,128], (5) CaM-dependent mTORC1 reactivation to prevent cell death by increasing protein synthesis and promote lysosome reformation [22,23], and (6) CaN/TFEB activation to continuously supply lysosome and autophagy proteins [24,25,47] (Figure 3). Because TRPML1 is also a target of TFEB, a positive feedback is established to largely potentiate autophagy during stress [24,25]. Thus, TRPML1 is involved in several steps of autophagy including autophagosome formation, autophagosome maturation, autolysosome degradation, and autophagic lysosome reformation.

In addition to TRPML1, TRPML3 also takes part in autophagy regulation. TRPML3 has been found in the plasma membrane and multiple intracellular compartments, including autophagosomes, early endosomes, late endosomes, and lysosomes. The multiple compartmental localization of TRPML3 suggests that TRPML3 is dynamically expressed in different compartments and plays a role in membrane trafficking. Indeed, TRPML3 is accumulated in the plasma membrane upon inhibition of endocytosis and is recruited to autophagosomes upon induction of autophagy, thereby regulating endocytosis and autophagy [129]. Specifically for autophagy, TRPML3 overexpression increases while its knock-down or expression of the channel-dead dominant negative TRPML3 reduces autophagy [129]. Mechanistically, emerging evidence suggests that palmitoylation at its C-terminal region is required for TRPML3′s function in autophagosome formation, potentially by controlling its trafficking to autophagic structures [130], where TRPML3 may promote autophagosome maturation by providing Ca²⁺ in the fusion process through a specific interaction with GATE16, a mammalian ATG8 homologue [131].

4.2. TPC Channels in Autophagy

The role of TPCs in autophagy has been conflicting. Pereira et al. [132] showed that in astrocytes, NAADP and TPC2 overexpression increased the levels of autophagy markers, LC3 and beclin-1, and NAADP-mediated increases in LC3II levels were reduced in cells expressing a dominant–negative TPC2 construct. In the meantime, Leucine-rich repeat kinase 2 (LRRK2), an important regulator of autophagy involved in late-onset familial Parkinson’s disease (PD) [133], activated the CaMKKβ)/AMPK pathway, which was followed by a persistent increase in autophagosome formation. These effects were mimicked by the lysosomal Ca²⁺-mobilizing messenger NAADP and reversed by an NAADP receptor antagonist or expression of dominant–negative receptor constructs, suggesting that TPC2-mediated lysosomal Ca²⁺ release may promote autophagy [134]. However, skeletal muscles from animals lacking TPC2 displayed an enhanced autophagy flux [135]. In addition, loss of TPCs did not appear to have gross defects in autophagy in the liver, heart, and macrophages [65]. There, the role of TPC2 in autophagy may be dependent on the conditions. Interestingly, Cang et al. suggested that ATP/mTOR phosphorylates and inhibits TPCs, thereby acting as a nutrient sensor to detect nutrient status in response to intracellular ATP and mTOR levels [65]. In contrast, in skeletal muscle, the loss of TPC2 leads to a reduced mTOR [135]. It seems that TPC2 and mTOR form a feedback regulatory loop in response to nutrient status.

4.3. Other Channels in Autophagy

Although most voltage gated Ca²⁺ channels (VGCCs) are found in the plasma membrane of excitable cells, P/Q-type VGCCs are recently reported to be expressed in lysosomes of both mice and fruit flies. Loss of VGCC leads to defects in autophagosome–lysosome fusion, indicating an important role of Ca²⁺ flux through this channel in autophagy [64].

5.1. TRPMLs in Cancer

Recently, three groups have suggested independently that TRPML1 is required for tumor progression. Jung et al. [151] showed that TRPML1 expression was significantly elevated in HRAS-positive tumors and inversely correlated with patient prognosis. TRPML1 knockdown or inhibition selectively reduced the proliferation of cancer cells that express oncogenic but not wild-type HRAS. Mechanistically, they suggested that TRPML1 promotes cancer development by mediating cholesterol de-esterification and transport to maintain oncogenic HRAS in signaling-competent nanoclusters at the plasma membrane. In the meantime, Xu et al. [155] reported that in triple-negative breast cancer (TNBC), the expression level of TRPML1 was upregulated, promoting tumor proliferation via activating mTORC1 pathway. This is in agreement with previous findings that Ca²⁺ passing through TRPML1 is required for mTORC1 activation and cell growth [22,23]. In TNBC [155], TRPML1 also promoted lysosomal exocytosis [161,162,163,164], releasing lysosomal ATP [68,163,165] to the tumor microenvironment to facilitate cancer cell migration and invasion. Knockdown or inhibition of TRPML1 dampened tumor growth, cell migration, and invasion. Inversely, Kasitinon et al. [156] suggested that TRPML1 negatively regulated mTORC1 signaling to preferentially promote the survival and proliferation of melanoma cells, potentially by sustaining macropinocytosis and avoiding proteotoxic stress. Therefore, TRPML1 is necessary for cancer development by regulating multifaceted cellular signaling pathways. In line with this, TRPML1 inhibitor ML-SI1 has successfully suppressed the development of TNBC [155] and cancers bearingHRAS mutations [151]. Future studies should focus on optimizing known TRPML1 inhibitors (Table 1) and developing new drugs that specifically target on TRPML1 to treat some cancers.

Notably, the clinical course of patients with cancer is also related to the TRPML1 expression level. Elevated TRPML1 expression level is reported to associate with the poor prognosis of pancreatic ductal adenocarcinoma (PDAC) patients. Overall survival rate and recurrence-free survival are significantly lower in patients with high TRPML1 expression as compared with patients with low TRPML1 expression [166].

Although TRPML1 is often upregulated in cancer cells to promote cancer generation in glioblastoma TRPML1 agonist, MK6-83, reduce cell viability, and promote caspase-3-dependent apoptosis. Blocking TRPML1 dependent Ca²⁺ release or silencing TRPML1 abrogated these effects. Loss or reduction of TRPML1 transcripts strongly correlates with short survival in glioblastoma patients, suggesting that the reduction of TRPML1 expression may be negatively linked to prognosis for glioblastoma patients [167]. Therefore, the role of TRPML1 in cancer development is dependent on the types of cancers.

TRPML2 has been linked to glioma, because a high level of TRPML2 was detected in glioma tissues, and because its expression level increased with pathological grades [158]. Mechanistically, TRPML2 promoted tumor cell viability by inhibiting caspase-3 activity and increased proliferation through AKT and ERK1/2 phosphorylation. Silencing and knock-down of TRPML2 reduced proliferation of tumor cells and induced apoptosis [158].

The role of TRPML3 in cancer development has not been well studied. Wu et al. [168] reported that TRPML3 level is significantly downregulated in pancreatic adenocarcinoma tissues compared with non-tumor tissues. However, in squamous cell carcinoma and hepatocellular carcinoma, TRPML3 expression level was reported to be upregulated [169]. Therefore, further studies are needed to clarify the role of TRPML3 in different cancer types.

5.2. TPCs in Cancer

Emerging evidence has also suggested a role of TPCs in cancer development. Early studies suggested that TPC2 expression is increased in oral squamous cell carcinoma cell lines [170]. Later studies further suggested a link between TPC2 and melanoma [171,172], bladder cancer, leukemia, hepatocellular carcinoma [173], and breast cancer [174,175]. Suppressing TPC2 by siRNA or inhibitors reduced cancer cell migration and adhesion in vitro and decreased lung metastases of cancer cells in vivo [173,176]. Mechanistically, TPC2 may regulate autophagy [175] and β1-integrin recycling [173] to affect cancer progression. Interestingly, growing evidence has suggested that vascular endothelial growth factor (VEGF), the angiogenic factor, plays an important role in cancer progression by regulating vascularization. By using a murine model of VEGF-secreting melanoma, application of ned-19, an NAADP inhibitor, strongly inhibits tumor vascularization, growth, and metastases. At cellular level, ned-19 inhibits cell viability, proliferation, and migration; at molecular level, ned-19 suppresses VEGFR2 expression and VEGF-mediated lysosomal Ca²⁺ release in melanoma cells [176]. In agreement with the role of VEGF in angiogenesis, other studies suggest that in endothelial cells, VEGF induces lysosomal Ca²⁺ release through NAADP/TPC2 to regulate angiogenesis [177,178]. Altogether, these data suggest that VEGF promotes cancer progression by activating VEGFR2/NAADP/TPC2-mediated Ca²⁺ signaling pathway in both tumor cells and endothelial cells.

An earlier study showed that TPC1 transcripts are significantly higher than TPC2 transcripts in the SKBR3 human breast cancer cell line, highlighting the link between TPC1 expression and tumorigenicity [62]. Indeed, a recent study has suggested that NAADP-mediated TPC1 lysosomal Ca²⁺ release mobilizes ER Ca²⁺ via IP3R, subsequently promoting the proliferation of metastatic colorectal cancer (mCRC) cells by activating ERK and the PI3K/AKT signaling pathways [179].

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