Abstract

While patient-specific targeting of cellular growth and viability pathways dominates current approaches in anti-cancer therapeutics development, appreciation for the strategy of targeting transformation-dependent alterations in cellular organelle structure and function continues to grow. Here we discuss the lysosome as an anti-cancer target, highlighting its role as a key mediator of cell death. As the major degradative compartment of the cell, the lysosome houses dozens of destructive enzymes and is responsible for the breakdown of both internal and external molecules and particles; however, until relatively recently the contribution of the lysosome to cellular death mechanisms has been largely overlooked. Renewed interest in the therapeutic potential of lysosomal rupture to combat cancer has led to development of lysosome-disrupting agents that induce lysosomal membrane permeabilization (LMP), cathepsin protease release, and subsequent lysosome-dependent cell death (LDCD), now distinguished as a bona fide cell death process. Here, we present the basic biology, structure, and function of the lysosome, with particular emphasis on the transformation-associated alterations that sensitize cancer cell lysosomes to membrane rupture. We further describe the lysosome’s role in cell death and comprehensively outline emerging therapeutic strategies that exploit lysosomes for the treatment of a variety of malignancies.

INTRODUCTION

Using subcellular fractionation based purely on biochemical criteria, de Duve and colleagues (1955) made the serendipitous discovery of the lysosome (1, 2), an achievement deemed worthy of the Nobel Prize in Physiology (1974). Upon observation that liver-derived acid phosphatase exhibited latent activity following homogenization, it was deduced that a membrane-bound structure must normally sequester it, and potentially other degradative hydrolases, from their substrates (2, 3). Indeed, the lysosome harbors some 60 lytic enzymes (4) capable of degrading proteins, nucleic acids, polysaccharides, and lipids. Subsequent investigations determined that lysosomes serve as the terminal compartment for the degradation of extracellular materials taken up by endocytosis and phagocytosis and the digestion of intracellular constituents isolated during autophagy (5, 6). We now appreciate that lysosomes are more than cellular refuse depots; they are fundamental components of dynamic physiologic processes such as plasma membrane repair, bone and tissue remodeling, matrix degradation, inflammatory responses, antigen presentation, cholesterol homeostasis, nutrient sensing and metabolism, cell signaling, growth factor recycling, and programmed cell death (7–23). These processes differentially rely on fusion with endocytic vesicles or the regulated release of lysosomal hydrolases into the cytosol via lysosomal membrane permeabilization (LMP) or into the extracellular space via lysosomal exocytosis. A summary of the lysosome’s various functions is illustrated in Figure 1.

Figure 1

Functions of the lysosome. Lysosomes regulate cell function by internalizing and degrading pathogens, receptors, cellular debris, etc. via endocytosis and phagocytosis (upper left) and autophagy (upper right). They also transmit materials to the cell (more...)

Of note are observations that the quantity, composition, and complement of lysosomal hydrolases are often augmented with cancer pathologies. Along these lines, lysosomal heparanase and cathepsins promote cancer cell proliferation, angiogenesis, and metastasis, suggesting that these and other lysosomal enzymes are of potential clinical significance (24, 25). The therapeutic implications of lysosomal hydrolases were recognized decades ago, with seminal investigations describing enhanced activities of lysosomal enzymes in solid tumors as compared to their tissues of origin, with specific enzymes (i.e., beta-glucuronidase) favoring tumor cell invasiveness (26). Perhaps it is not surprising then that cancer cells often exhibit an expansion of the lysosomal compartment (24, 27, 28), a feature that would enhance tumor aggressiveness. However, such distinction may also provide a rational basis for therapeutic intervention. Cancer-associated lysosomes are more fragile than their normal counterparts due in some measure to increases in hydrolytic enzymes and fundamental changes in the composition of the lysosomal membrane (29–31). Based on the concept that the lysosome may represent a ‘suicide-bag’ as first proposed by de Duve (32), the instability of cancer-associated lysosomes may lend to enhanced cellular susceptibility to LMP, coincident release of destructive hydrolases into the cytosol and ultimate cell demise by either apoptotic or non-apoptotic cell death mechanisms.

Herein, we review the fundamentals of lysosome physiology, composition, and function in cell death, and connect cancer-associated changes in the expression and activity of lysosomal components with a particular focus on the therapeutic opportunities they may provide for breast and other tumor types.

LYSOSOMAL STRUCTURE, DISTRIBUTION, AND IDENTIFICATION

Lysosomes are typically less than 1 μm in diameter and contribute up to 0.5% of the total intracellular volume of many eukaryotic cells, although this may vary depending upon cell type (i.e., macrophages), energetic state, or degradative requirements (33–35). Unlike other organelles, lysosomes cannot be identified based on uniform morphologic criteria, as there is significant variation in their size, architecture, and morphology depending upon nutrient availability, for example, autophagy (36–39). Significant augmentation of lysosome volume, abundance, and structure also occurs during certain pathologic states, for example, lysosomal storage diseases (40) and cancer (24, 41), or following experimental manipulations that inhibit enzymatic digestion such as overloading with non-physiologic substrates such as sucrose (42), administration of cationic amphiphilic drugs (CADs (43–45)), or treatment with aminoglycoside antibiotics (46). Interestingly, lysosomes at peripheral locations can partially change their intracellular pH (47, 48), a feature that may be co-opted by some cancer cells to facilitate constitutive mTOR signaling (38) or modulate extracellular acidity to enhance invasion (49, 50).

By electron microscopy, lysosomes are identifiable as either tubular or spherical membrane-bound structures with cores of variable densities, amorphous granular material, or membrane whorls (34, 51). Biochemically, lysosomes are defined by the presence of multiple hydrolytic enzymes (32) which may vary between tissue type (51) and pathology (25, 40). Lysosomes may be distinguished from endosomes by their pH, calcium content, abundance of lysosomal-associated membrane proteins LAMP-1 and LAMP-2, and lack of mannose-6-phosphate receptors (34, 52–54). Fluorescent dyes that accumulate in acidic vesicles––such as LysoTracker Red and Acridine Orange––effectively label lysosomes, however other acidic vesicles such as endosomes and autophagosomes may be concomitantly labeled to varying degrees (55).

LYSOSOME COMPOSITION

Lysosomes can degrade a vast array of structurally diverse macromolecules into their constituent components. Following degradation, substances either diffuse or are transported out of the lysosome into the cytosol where they become fuel for metabolism or substrates for biosynthetic pathways (5). This dynamic recycling process requires the coordinated action of the lysosomal acid hydrolases with integral, peripheral, and transiently-associated proteins as discussed in the following sections.

LYSOSOMES IN CELL DEATH

Cell death is classically defined by morphological criteria: apoptotic cells display cellular shrinkage, nuclear fragmentation, and condensation into apoptotic bodies for clearance by phagocytosis; autophagy-dependent cell death involves cytoplasmic vacuolization and autophagosome formation, followed by lysosomal degradation; necrosis manifests as organelle swelling, plasma membrane breakdown, and disintegration of cellular structures (153). However, investigations into the precise biochemical and functional underpinnings of cell death processes have revealed distinct “regulated” cytotoxic programs and prompted a diversification of nomenclature. Lysosome-dependent cell death (LDCD), characterized by lysosomal destabilization and requiring LMP, is now distinguished as a subclass of programmed cell death (153). Though lysosomal rupture has been observed as an ultimate consequence of canonical cell death processes (154), primary LMP activates a death program in LDCD and can be differentiated by novel assay systems (155, 156). LMP does not generate defining morphological alterations (157) and is therefore classified at the molecular level by release of lysosomal luminal contents including proteolytic cathepsin enzymes to the cytosol, where cathepsins function in a variety of contexts as cell death executioners (158). However, the precise mechanisms leading to loss of lysosomal membrane integrity and protease translocation to the cytosol are not fully elucidated for the majority of LMP stimulants. Activities of pore-forming toxins such as venoms, bacterial toxins, and viral entry proteins are fairly straightforward; these compounds can disrupt membrane dynamics from within the lysosome following their uptake into the endolysosomal system and activation at low-pH, or alternatively induce pore formation from the cytosol (158, 159). Lysosomotropic detergents are well-studied LMP-promoting agents that function by directly disrupting membrane dynamics leading to organelle leakage or by impairing function of lysosomal lipases (158). Under physiological conditions, LDCD contributes to tissue remodeling during mammary gland involution (160) and regulates immune cell clearance following inflammation (161) or bacterial infection (162). Moreover, LDCD is associated with a variety of pathological states (153).

LYSOSOMES IN CANCER

As cancer is broadly characterized by rapid cell proliferation and upregulated cell survival mechanisms to combat cellular damage, many transformation-associated changes at the level of the lysosome serve to protect the cell from LMP and LDCD. Paradoxically, the opposite effect is also observed, where neoplastic cells can sacrifice lysosomal stability in order to increase their tumorigenic potential or aggressiveness (24). Therefore, it is critical to understand the complex regulation of LMP in cancer cells in order to pharmacologically hedge the balance towards LDCD for therapeutic benefit.

Cancer cells rely on increased metabolism to sustain their rapid proliferation. The lysosome serves as a key regulator in this process and helps satisfy the catabolic need for building blocks for growth and neoplastic anabolic drive. The outer lysosomal membrane serves as a docking site for mTORC1, a signaling complex regulated by available nutrients in the cytoplasm. mTORC1 signals the upregulation of lipid and protein biosynthesis, as well as the transcription of pro-tumorigenic and anti-apoptotic regulators of the cell cycle (102, 208). Loss of several tumor suppressors including p53, PTEN, NF1 and TSC1/2 have been shown to activate mTORC1 (209). Furthermore, the lysosome is responsible for executing autophagy, one of the cell’s primary mechanisms of catabolism (210). Several cancers have engaged mechanisms to constitutively activate autophagy, such as in Ras-driven pancreatic cancers. This increased baseline level of autophagic flux allows for more rapid clearance of toxic metabolites that build up as a consequence of increased metabolism (211–213). Therefore, inhibition of autophagy could potentiate induction of LMP in such tumors.

The high metabolic activity of cancer cells presents another weakness in lysosomal regulation. Swift protein turnover demanded by rapidly dividing cancer cells leads to excessive intralysosomal accumulation of iron (214). Iron accretion alone is sufficient to sensitize the lysosome to LMP; however, Fenton-type reactions with H₂O₂ can generate additional ROS and further destabilize lysosomal membranes through lipid oxidation. Coupled with the well-documented increase in ROS production in cancer cells and augmented cytoplasmic levels of cathepsins, lysosomal iron accumulation sensitizes tumor cells to LMP and LDCD (215). Other transformation-associated alterations in cancer cell lysosomes include increases in expression of lysosomal enzymes, changes in lysosomal morphology and localization, and modifications in lysosome-associated proteins. Cathepsins are highly expressed in cancer cells and are localized to the cell periphery in secretory lysosomes, where they can be secreted into the surrounding extracellular environment through a mechanism similar to the lysosomal exocytosis that allows the formation of invasive protrusions in C. elegans development (216). Once in the extracellular space, they wreak havoc by cleaving a variety of adhesion proteins, degrading the basement membrane, and releasing sequestered growth factors such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), leading to neoplastic progression through invasion, angiogenesis, and metastasis (41, 217, 218). Additionally, downregulation of a potent regulator of pericellular cathepsin accumulation, M6PR, in a rat cell model of hepatocellular carcinoma abrogates inhibition of pro-neoplastic cathepsin activity (219). High concentrations of cathepsins predict increased tumor aggressiveness and poor prognosis in many tumor types such as breast cancer, lung and colorectal carcinomas, and gliomas (220–223). However, increased levels of cytosolic cathepsins also sensitize the cell to LDCD (224). Increased lysosomal cathepsin activity leads to decreased LAMP-1 and -2 levels in ERK-, ErbB2-, and K-Ras-driven models of cancer, reducing lysosomal membrane stability and rendering the organelle susceptible to LMP (114). These cancer-associated vulnerabilities illuminate a potential therapeutic window to selectively target tumor cells.

As previously noted, lysosomes are alternatively localized within transformed cells; the switch from a perinuclear position to the plasma membrane facilitates secretion of toxic contents into the extracellular space, promoting extracellular acidification and activation of secreted lysosomal hydrolases (41). Increased expression of v-ATPase in metastatic tumor cells also contributes to extracellular acidification (225). Additionally, cancer cells exhibit increased lysosomal size, a phenomenon correlated with the metastatic potential of breast cancer cells (28). Once again, these tumorigenic changes compromise lysosomal stability, sensitizing tumor cells to LMP (28). Problematically, some forms of cancer have developed mechanisms to overcome this increased sensitivity to LMP. Breast cancer cells show elevated expression of Hsp70 (226), which has been shown to rescue lysosomal membrane integrity by stabilizing intralysosomal aSMase interaction with the critical lipase cofactor BMP (30, 215). Likewise, mammary-derived growth inhibitor (MDGI), which contributes to maintenance of lysosomal integrity, is a marker of invasiveness in human glioblastoma patient-derived cells that are resistant to chemoradiation. Silencing MDGI leads to alterations in lysosomal membrane lipid composition through reduced trafficking of polyunsaturated fatty acids into the lysosomes, leading to eventual LMP-dependent cell death (227). Along these lines, targeting Hsp70 or other molecules critical to lysosome stability and function could prove to be promising therapeutic strategies.

Localization of transport proteins to the lysosomal membrane in transformation confers therapeutic resistance via active sequestration and inactivation of antineoplastics within the lysosomal lumen. Canonically, members of the ATP-binding cassette (ABC) family of transporters reside in the plasma membrane where they expel cytoplasmic antineoplastics, but some cancers (e.g., leukemia, breast and cervical cancers) exhibit lysosomal expression of transporters like P-glycoprotein (P-gp or ABC1), leading to drug sequestration in the lysosome (228–230). Inhibition of P-gp in cancer cells restores sensitivity to the sequestered drugs and hyper-sensitizes cells to chemotherapeutic death (228, 230). Overexpression of ABCA3 correlates with poor prognosis in acute myeloid leukemia patients, and ABCA3 localizes to lysosomes in a chronic myeloid leukemia cell line (231, 232). The transport protein ATP7B, a copper transporter, is overexpressed in many cancers (233) and serves to sequester and exocytose platinum-based antineoplastics (234, 235). Overall, the dynamic changes in cancer-associated lysosomes reveals a wide range of possible therapeutic options for exploration (236).

MODULATION OF LMP AND ITS THERAPEUTIC POTENTIAL

Depletion of cancer cells via LMP is an attractive therapeutic strategy, holding particular promise for combating apoptosis-resistant cancer cell populations (237). Initial interest in this regard was sparked by realization of the degradative potential of lysosomes (1), catalyzing the search for pharmacologic agents that would destabilize the lysosomal membrane to kill cancer cells from the inside. Cholesterol and hydrocortisone were identified as stabilizing agents (32), while weakly basic amines with long hydrophobic tails disturbed membrane structure and induced LMP (238–240). However, enthusiasm quickly waned upon recognition that lysosomes were a ubiquitous feature of nearly all cells (excluding erythrocytes (34)), and would not permit the distinction between normal and cancer cells (32). Interest has since reignited following more recent studies that suggest cancer-associated lysosomes express unique features (i.e., size, hydrolase content, membrane fragility) that may make them suitable for targeting. Numerous lysosome-disrupting agents are currently under investigation or in clinical development for cancer and other indications (237, 241), though clinical data demonstrating efficacy of these approaches is limited. This section outlines select agents known to induce LMP, with a particular emphasis on their potential as anti-cancer therapeutics. General mechanisms of LMP induction are illustrated in Figure 2.

Figure 2

Mechanisms of LMP induction. (A) The lysosomal membrane is expanded to show detail. Carbohydrates on lysosomal associated membrane proteins (LAMPs) and lysosomal integral membrane proteins (LIMPs) form the protective glycocalyx. Also, resident within (more...)

Sphingolipids

Mounting evidence suggests that LMP occurs following specific changes in the composition of membrane lipids and major lysosomal proteins (114). Particularly interesting data has recently come to light suggesting that cancer cells have perturbed lipid species as compared to their normal counterparts, a feature that may permit their selective depletion. Along these lines, the lysosomotropic detergent siramesine and similar compounds directly induce LMP and non-apoptotic cell death in transformed cells but not in oncogene-depleted (‘detransformed’) or non-transformed variants (29, 282). These effects were universal across all cancer types tested (breast, ovary, prostate, cervix and bone (29)). Intriguingly, similar cancer specific effects were not found for other compounds that also induce LMP (i.e., LLOMe, sphingosine) or neutralize pH (concanamycin A) (29), although the lack of specificity may be related to the dose used (283).

Ostensibly, siramesine cytotoxicity is mediated by the displacement of aSMase (29), normally responsible for the breakdown of sphingomyelin to ceramide at the inner lysosomal membrane (134). Augmentation of aSMase activity occurs in stressed normal cells following induction of heat shock protein 70 (Hsp70), which then binds the glycerophospholipid BMP to activate aSMase at the lysosomal membrane (30). The constitutive elevation of Hsp70 has been detailed for a number of cancer types, and is associated with resistance to caspase-dependent and -independent cell death and poor prognosis (284–287). Bolstered aSMase activity appears to contribute to lysosomal integrity (29), making it a particularly attractive therapeutic target. Accordingly, exposure to siramesine (29) or Hsp70 small molecule inhibitors (288) results in reductions in aSMase activity, induction of LMP, caspase-independent cell death and enhanced sensitivity to chemotherapeutics. In agreement with siramesine-mediated aSMase inhibition, depleted Hsp70 induces effects that are cancer cell specific (286, 289–292). It is likely that aSMase inhibition perturbs lipid ratios (293), leading to membrane fragility and a propensity for LMP (29). This postulate is further supported by studies suggesting that augmented sphingomyelin content alone destabilizes lysosomal membranes (30), is selectively toxic to transformed cells (294), inhibits autophagic flux (295), and impairs intracellular vesicle and plasma membrane fusion events (296). Destabilized lipid content following aSMase inhibition also affects signaling events at the plasma membrane, including the clustering and signaling of K-Ras (293), a protein with a dominant role in cell proliferation and survival. These data suggest that aSMase inhibition may not only be cancer cell specific (29), but may also be particularly well suited for K-Ras-driven cancers (i.e., pancreas, colon and lung), which currently lack targeted therapeutic options (297).

The clinical significance of sphingolipid species is further substantiated by observations that perturbed ceramide clearance was directly correlated with reduced chemotherapeutic sensitivity (298). As such, modification of ceramide levels by enhancing de novo biosynthesis or modulating aSMase activity have also been suggested as potential anti-cancer strategies to overcome imbalances in lysosomal ceramide (298–301). Although a clear link has yet to be established, a recent study demonstrated that markedly enhanced aSMase potentiates the accumulation of ceramide and triggers cathepsin B release via LMP upstream of apoptosis (176). Importantly, cathepsin B catalyzes the degradation of XIAP (X-linked inhibitor of apoptosis) (176), the upregulation of which has been associated with therapeutic resistance and poor survival (302–304).

It is worthwhile to note that experimental modulation of aSMase activity appears to produce seemingly contradictory results. On the one hand, the depletion of aSMase results in sphingolipid accumulation, ceramide depletion, LMP, and non-apoptotic cell death (29), whereas on the other hand its overexpression precipitates ceramide accumulation, LMP, and apoptosis (176). As such, it is likely that lysosome integrity depends upon the precise balance of sphingolipid species. Moreover, it is conceivable that there are factors modified under conditions of aSMase depletion or overexpression that await further investigation. For example, sphingosine accumulation inhibits cholesterol export (305), which may have implications for signaling events at lysosome-associated lipid raft domains or in membrane dynamics. Moreover, modifications to sphingosine or ceramide may generate either sphingosine-1-phosphate or sphingosine, respectively. Sphingosine-1-phosphate binds to G-coupled protein receptors to regulate growth, survival and migration of cells, and is associated with malignant transformation (306). Sphingosine was shown to induce LMP and programmed cell death (307–309), albeit nonspecifically (29). It was proposed that accumulated sphingosine permeabilizes the membrane in a detergent-like fashion, resulting in cell death (310). A potential mechanism is outlined in Figure 3 that discusses the intricate balance of sphingolipids in LMP induction.

Figure 3

Membrane stabilization and permeabilization is dependent on the balance of sphingolipids in lysosomes. Negatively charged bis(monoacylglycero)phosphate (BMP; shown in teal) is enriched in membranes of intraluminal lysosomal vesicles and provides docking (more...)

CONCLUSION

The lysosome is clearly more than a cellular garbage disposal, contributing to dynamic processes that are essential to both normal physiologic function and disease pathology. Cancer-associated changes in lysosomal structure and function may bolster therapeutic resistance but may also be the gateway to cancer cells’ ultimate demise. Indeed, emerging data suggests the lysosome is potentially a powerful anti-cancer target, given specific alterations in cancer cells that are not seen in non-transformed counterparts. Moreover, cancer cells frequently evade therapy-induced apoptosis due to intrinsic or acquired mutations in caspase-dependent pathways; thus, utilization of LDCD and other caspase-independent cell death programs will be critical in the future development of cancer therapeutics. Nevertheless, a number of questions still remain with respect to cancer-associated lysosome signaling, membrane dynamics, ion regulation, and the precise role of LMP in cell death, which have limited the number of lysosome-targeted therapeutics transitioning from preclinical study to clinical development. The dual functionality of cathepsin activation in cancer cell invasion and LDCD is a critical area requiring further investigation, as cathepsins are important mediators of both pro-tumorigenic and pro-death processes, depending on context. Substantial progress on these and other fronts will likely be fueled by continued advances in methods for the detection and quantification of lysosome-associated events.

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Cite this chapter as: Berg AL, Rowson-Hodel A, Wheeler MR, Hu M, Free S, Carraway KL III. Engaging the Lysosome and Lysosome-Dependent Cell Death in Cancer. In: Mayrovitz HN. editor. Breast Cancer. Brisbane (AU): Exon Publications. Online first 21 Feb 2022.

Doi: https://doi​.org/10.36255​/exon-publications-breast-cancer-lysosome

*

These authors contributed equally to this work.

Conflict of Interest: The authors declare no potential conflict of interest with respect to research, authorship and/or publication of this chapter.

This work was supported by NIH grant R01 CA250211 (K.L.C.).