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Halaby, R. Lysosomal Membrane Permeabilization. Encyclopedia. Available online: https://encyclopedia.pub/entry/16307 (accessed on 29 November 2023).
Halaby R. Lysosomal Membrane Permeabilization. Encyclopedia. Available at: https://encyclopedia.pub/entry/16307. Accessed November 29, 2023.
Halaby, Reginald. "Lysosomal Membrane Permeabilization" Encyclopedia, https://encyclopedia.pub/entry/16307 (accessed November 29, 2023).
Halaby, R.(2021, November 23). Lysosomal Membrane Permeabilization. In Encyclopedia. https://encyclopedia.pub/entry/16307
Halaby, Reginald. "Lysosomal Membrane Permeabilization." Encyclopedia. Web. 23 November, 2021.
Lysosomal Membrane Permeabilization
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This entry is adapted from the peer-reviewed paper 10.3390/medicines8110069

Cancer is the second leading cause of death worldwide. Many tumors eventually become resistant to hormones, chemotherapy, and radiation by avoiding apoptosis.

cancer lysosomes lysosomal membrane permeabilization

1. Introduction

Cancer is the second leading cause of death worldwide. Many tumors eventually become resistant to hormones, chemotherapy, and radiation by avoiding apoptosis [1]. Cancer cells become resistant to anticancer therapies by mutating pro-apoptotic genes and upregulating anti-apoptotic genes. This chemoresistance is one of the biggest reasons why chemotherapeutic therapies fail. Treatments such as chemotherapy and radiation are known to have untoward side effects. The use of natural products may have fewer side effects and less toxicity than conventional chemotherapeutic drugs [2]. The chemoprotective properties and low cytotoxicity of natural products make them attractive resources to use against malignancies. It is desirable to identify more natural compounds with anticancer activity. The antineoplastic actions of these natural compounds are mediated by their ability to induce apoptosis in cancer cells [3]. Apoptosis or programmed cell death is regulated by a balance of activation of proapoptotic genes, such as executioner caspases (including caspases −3, −6, and −7 [4][5]) and antiapoptotic genes, such as Bcl-2 and XIAP. This review will focus on the ability of certain natural products to induce apoptosis by triggering lysosomal membrane permeability (LMP). Lysosomal-mediated apoptosis is an attractive way to target neoplastic cells since cancer cells have larger and thus more fragile lysosomes compared to wild-type cells [6][7]. Moreover, cancer cells have a higher reliance on lysosomes for proliferation, metabolism, and adaptation to stressful environments relative to normal cells. Indeed, cancer cells can increase the biogenesis of lysosomes, thus affecting the number of lysosomes [8][9]. Unlike mutating genes, neoplastic cells cannot alter their lysosomes, rendering these organelles as putative sites for directing novel anticancer treatments. Thus, lysosomal cell death offers an alternative mechanism to kill tumor cells that become resistant to standard chemotherapy. Lysosomes have been reported to play a role in sequestering basic chemotherapeutic drugs in their acidic lumens, thus lowering the effective drug concentrations to target sites, such as the nucleus [10][11]. Clearly, further investigations are warranted to decipher the exact roles played by lysosomes in cancer therapy.
Lysosomes are acidic organelles that contain at least fifty hydrolytic enzymes including proteases, nucleases, glycosidases, and lipases [12]. Lysosomes digest unwanted materials and damaged organelles. These hydrolases can degrade the entire contents of a cell, which is why they must perform cellular digestion within the lysosomal membrane. Leakage of lysosomal enzymes into the cytosol can initiate apoptosis [13][14][15]. Furthermore, cleavage of Bid and degradation of Bcl-2 by lysosomal cathepsins can promote mitochondrial membrane permeabilization and caspase activation, which are hallmarks of apoptosis [16][17]. Lysosomal hydrolases can also initiate the intrinsic apoptotic pathway independent of Bid cleavage [15]. The most relevant lysosomal proteases are cathepsins B, D, and L; they are abundant in lysosomes and can remain active at neutral pH values [16][18]. The intrinsic (mitochondrial) apoptotic pathway involves the release of intermembrane space proteins such as cytochrome c and Smac/DIABLO and activation of executioner caspases [19][20][21].

2. Lysosomal Membrane Permeabilization

Mounting evidence suggests that lysosomes are good molecular targets for cancer therapy [22][23][24]. The cytosolic translocation of lysosomal enzymes can be triggered by reactive oxygen species, lysosomotropic agents, and weak bases, including chemotherapeutic agents [25][26]. A recent study identified autophazole, a novel autophagy initiator that gets incorporated into lysosomes of cancer cells [27]. Autophazole induces the release of cathepsins from lysosomes, leading to apoptosis. Some anticancer agents are known to induce lysosomal-dependent cell death by modifying the lysosomal membrane integrity, including vincristine and siramisene [28][29].
The precise mechanisms responsible for regulating lysosomal membrane permeabilization (LMP) have yet to be elucidated. It is not known whether pores or channels form in the lysosomes. It has been confirmed that the following agents and signaling pathways can disrupt lysosomal membranes, namely reactive oxygen species [30], sphingosine [31], downregulation of Hsp70 [32], photodynamic therapy [33], and translocation of Bax into the lysosomal lumen [34]. Upon release into the cytosol via LMP, cathepsins degrade Bcl-2 and cleave Bid, triggering the mitochondrial apoptotic pathway [35]. Regardless of the trigger of LMP, it has been shown by several reports that cytosolic leakage of cathepsins precedes changes in the mitochondrial membrane potential [18][36].
Possible explanations for the control of LMP are emerging. One report confirmed the occurrence of LMP via galectin 3 puncta assay as well as cytoplasmic leakage of lysosomal enzymes [37]. A recent study provides a putative explanation for the regulation of LMP. Toll-like receptor 3 (TLR3) acts as a death receptor in several cancer cell lines [38][39]. TLR3 can activate the extrinsic apoptotic pathway via initiator Caspase-8 [40][41]. Caspase-8 can then subsequently activate downstream effector caspases such as Caspase-3 and trigger the intrinsic apoptotic pathway. Loquet et al. (2021) showed that cell lines deficient in Caspase-8 undergo an unconventional type of cell death characterized by permeabilization of the lysosomal membrane as the initial event [42]. Interestingly, TLR3 is localized in lysosomes [42] and might provide a way to execute LMP in cancer cells that are defective in Caspase-8 or perhaps independent of Caspase-8.

3. Natural Products Induce Lysosomal Membrane Permeabilization in Cancer Cells

Venkatesan et al. reported that Pinus radiata bark extract (PRE) induces apoptosis in MCF-7 breast cancer cells [43]. This group demonstrated that PRE-induced cell death was accompanied by lysosomal membrane permeability and concomitant cytosolic release of cathepsins. Furthermore, this cell death was observed to be caspase-independent. Although this cell death did not involve caspase activation, it possessed certain hallmarks of apoptosis. Namely, externalization of phosphatidylserine, cytoplasmic vacuolation, and chromatin condensation were observed.
Oleocanthal-rich compounds such as olive oil have been demonstrated to induce cell death in various cancer cells [44]. Moss et al. showed that low density lipoproteins reconstituted with the natural omega 3 fatty acid docosahexaenoic acid [45] (LDL-DHA) were selectively toxic to liver cancer cells and not normal hepatocytes [46]. This study demonstrated that basal levels of oxidative stress were higher in malignant TIB-75 cells compared to normal TIB-73 cells. The increase in reactive oxygen species (ROS) and iron-catalyzed reactions made cancerous liver cells susceptible to destabilization of their lysosomes. Another report demonstrated that DHA-treated cells induced lysosomal-mediated cell death in MDA-MB-231 breast cancer cells [47].
Monanchocidin A (MonA) is an alkaloid, initially isolated from the marine sponge Monanchora pulchra [48]. Dyshlovoy et al. demonstrated that MonA induces apoptosis in bladder and prostate cancer cells [49]. LMP was confirmed by release of cathepsin B into the extracellular space and disappearance of red fluorescence of acridine orange coupled with the appearance of green fluorescence. Non-malignant cells were less sensitive to MonA. Inhibitors of lysosomes and lysosomal enzymes were able to block the cytotoxic effects of MonA, further supporting the role of LMP in MonA-treated cells.
Triptolide (TPL), the active compound from the Chinese herb Tripterygium wilfordii Hook F, has been used in traditional Chinese medicine for over two centuries. TPL activates lysosomal-mediated apoptosis in MCF-7 breast cancer cells [50]. MCF-7 cells are a good model system to study lysosomal cell death because they lack caspase-3, a key pro-apoptotic executioner gene [51]. We have previously demonstrated in cell fractionation experiments that cytosolic levels of cathepsin B increase in triptolide-treated cells during early stages of apoptosis [50]. Owa et al. detected a shift from red fluorescence to green fluorescence in experimental cells stained with acridine orange [50]. These findings support the disruption of lysosomal membrane integrity by triptolide. We detected the subcellular localization of cathepsin B in the cytosol of MCF-7 cells via fluorescence microscopy in triptolide-treated cells [52]. In another report, TPL sensitized TRAIL-resistant pancreatic cancer cells to apoptosis by promoting LMP [53]. Taken together, these results demonstrate that TPL preferentially induces lysosomal disruption to target the death of cancer cells.

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