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• W1987672018 abstract "Cancer cells display lysosome hypertrophy, secreting lysosomal hydrolases for tumor progression. Hypertrophy renders lysosomes fragile, increasing lysosomal membrane permeabilization (LMP) tendency. In this issue of Cancer Cell, Petersen and colleagues show that lysosomal sphingomyelin content determines LMP and cationic drugs displace acid sphingomyelinase from lysosomal membranes, increasing tumor LMP and death. Cancer cells display lysosome hypertrophy, secreting lysosomal hydrolases for tumor progression. Hypertrophy renders lysosomes fragile, increasing lysosomal membrane permeabilization (LMP) tendency. In this issue of Cancer Cell, Petersen and colleagues show that lysosomal sphingomyelin content determines LMP and cationic drugs displace acid sphingomyelinase from lysosomal membranes, increasing tumor LMP and death. Early on after the discovery of lysosomes by Christian de Duve as a separate compartment that confines highly destructive hydrolases for the demolition and reutilization of cellular substituents, the concept that these structures might alternatively represent “suicide bags” was proposed (de Duve, 1983de Duve C. Eur. J. Biochem. 1983; 137: 391-397Crossref PubMed Scopus (346) Google Scholar). This led to an intense search for lysosomatrophic agents that might access this biology for therapeutic purpose. Although a set of lysosomal detergents with long hydrophobic tails and medium pK were defined as capable of inducing lysosomal membrane permeabilization (LMP) and thereby releasing the destructive power of hydrolases into the cytoplasm, this concept was rapidly retired, because it was not possible to assign lethal causality to these compounds based on LMP as opposed to postmortal lysosomal destruction (Miller et al., 1983Miller D.K. Griffiths E. Lenard J. Firestone R.A. J. Cell Biol. 1983; 97: 1841-1851Crossref PubMed Scopus (143) Google Scholar). In the interim, the field of cathepsin protease biology developed. Cathepsins represent a class of cysteine, serine, and aspartate proteases that segregate into lysosomes and, under homeostatic conditions, serve to reutilize polypeptides for ongoing cellular metabolic requirements. Lysosomes contain more than 50 cathepsins, and, as a class, they have been associated with various human pathologies, including cancer. Numerous cathepsins and other lysosomal enzymes, e.g., heparanase, have been strongly associated with cancer cell proliferation, angiogenesis, and metastasis (Kallunki et al., 2013Kallunki T. Olsen O.D. Jäättelä M. Oncogene. 2013; 32: 1995-2004Crossref PubMed Scopus (197) Google Scholar). Evidence indicates that, upon secretion, these tumor-promoting lysosomal enzymes act extracellularly. To accommodate this burgeoning need, tumor cells in general display enlargement of the lysosomal compartment. Mounting evidence for a role of lysosomal constituents in tumor progression has spawned numerous preclinical and clinical efforts to abort lysosomal enzyme action (Kallunki et al., 2013Kallunki T. Olsen O.D. Jäättelä M. Oncogene. 2013; 32: 1995-2004Crossref PubMed Scopus (197) Google Scholar). More recently, the focus has been on the notion that this expanded lysosomal compartment might represent a tumor vulnerability (Kallunki et al., 2013Kallunki T. Olsen O.D. Jäättelä M. Oncogene. 2013; 32: 1995-2004Crossref PubMed Scopus (197) Google Scholar). Substantive data indicate that tumor cell lysosomes are more fragile than normal lysosomes, i.e., they are more susceptible to LMP, leading to tumor demise by apoptotic and nonapoptotic death mechanisms. This lysosome fragility is posited (at least in part) to result from the extra burden of destructive enzymes contained within tumor cell lysosomes. Petersen et al., 2013Petersen N.H.T. Olsen O.D. Groth-Pedersen L. Ellegard A.-M. Bilgin M. Redmer S. Ostenfeld M.S. Ulanet D. Dovmark T.H. Lønborg A. et al.Cancer Cell. 2013; 24 (this issue): 379-393Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar; in this issue of Cancer Cell) have been major proponents of this latter concept over the past decade. Work by Petersen et al., 2013Petersen N.H.T. Olsen O.D. Groth-Pedersen L. Ellegard A.-M. Bilgin M. Redmer S. Ostenfeld M.S. Ulanet D. Dovmark T.H. Lønborg A. et al.Cancer Cell. 2013; 24 (this issue): 379-393Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and Kirkegaard et al., 2010Kirkegaard T. Roth A.G. Petersen N.H. Mahalka A.K. Olsen O.D. Moilanen I. Zylicz A. Knudsen J. Sandhoff K. Arenz C. et al.Nature. 2010; 463: 549-553Crossref PubMed Scopus (368) Google Scholar; in a recent publication in Nature), have made the novel observation that the sphingomyelin (SM) content of lysosomal membranes regulates membrane fragility and thus tendency toward LMP. Initial studies focused on the mechanism for the lysosome protective effect of HSP70. Kirkegaard et al., 2010Kirkegaard T. Roth A.G. Petersen N.H. Mahalka A.K. Olsen O.D. Moilanen I. Zylicz A. Knudsen J. Sandhoff K. Arenz C. et al.Nature. 2010; 463: 549-553Crossref PubMed Scopus (368) Google Scholar first tracked the trafficking of recombinant fluorescent HSP70 into lysosomal membranes. They determined that HSP70 bound preferentially to the endolysosomal membrane-specific anionic lipid, bis(monoacylglycer)phosphate (BMP). Because Konrad Sandhoff had previously shown that BMP binds acid sphingomyelinase (ASM) with high affinity (Linke et al., 2001Linke T. Wilkening G. Lansmann S. Moczall H. Bartelsen O. Weisgerber J. Sandhoff K. Biol. Chem. 2001; 382: 283-290Crossref PubMed Scopus (91) Google Scholar), thereby stimulating the enzymatic hydrolysis of SM to ceramide, Petersen et al., 2013Petersen N.H.T. Olsen O.D. Groth-Pedersen L. Ellegard A.-M. Bilgin M. Redmer S. Ostenfeld M.S. Ulanet D. Dovmark T.H. Lønborg A. et al.Cancer Cell. 2013; 24 (this issue): 379-393Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar made the conceptual leap that SM metabolism might regulate LMP. In a tour de force set of investigations, they showed that HSP70 binding to BMP stabilized the BMP-ASMase interaction, thereby lowering lysosomal membrane SM levels, which reduced membrane fragility (Kirkegaard et al., 2010Kirkegaard T. Roth A.G. Petersen N.H. Mahalka A.K. Olsen O.D. Moilanen I. Zylicz A. Knudsen J. Sandhoff K. Arenz C. et al.Nature. 2010; 463: 549-553Crossref PubMed Scopus (368) Google Scholar). An argument was thereafter made that HSP70 might be used therapeutically to stabilize point-mutated ASM in Niemann-Pick disease, an inherited disorder characterized by SM accumulation in lysosomes, lysosomal fragility, and either a progressive neurodegenerative course (type A) or progressive visceral organ abnormalities (type B). With these observations in hand and the emerging data suggesting that cancer cells manifest lysosomal traits analogous to those of NPD patients, Petersen et al., 2013Petersen N.H.T. Olsen O.D. Groth-Pedersen L. Ellegard A.-M. Bilgin M. Redmer S. Ostenfeld M.S. Ulanet D. Dovmark T.H. Lønborg A. et al.Cancer Cell. 2013; 24 (this issue): 379-393Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar began to explore the potential of attacking tumor cells by engaging SM metabolism. This group had been investigating the capability of the cationic drug (CAD) siramesine to induce LMP and cell death of tumor cells (Ostenfeld et al., 2005Ostenfeld M.S. Fehrenbacher N. Høyer-Hansen M. Thomsen C. Farkas T. Jäättelä M. Cancer Res. 2005; 65: 8975-8983Crossref PubMed Scopus (212) Google Scholar) and applied the lessons learned from HSP70 lysosomal biology to tumors (Figure 1). Using vector- and c-srcY527F-transduced NIH 3T3 murine embryonic fibroblasts (MEFs), evidence was provided that the hypersensitivity of the c-src-transduced MEFs to siramesine was distinct from that of sphingosine and Leu-LeuOMe, lysosomotropic detergents that also induce LMP, and was not due to neutralization of lysosomal pH per se. Rather, it appeared that siramesine acted like some other CADs that had been recently shown to displace ASM from the inner lysosomal membrane, resulting in hydrolytic cleavage of ASM. In fact, siramesine treatment leads to decreased ASM activity and increased SM content in c-src-transduced, but not vector-transduced, NIH 3T3 MEFs, rendering these SM-replete lysosomes susceptible to LMP and cell death. This susceptibility to siramesine appeared generic to tumor cells as compared to detransformed variants or isogenic normal cell lines. In a large set of in vitro and in vivo models, CADs, as a class, reproducibly antagonized tumor formation, growth, and/or metastases. From these data, it might have been predicted that tumor cells would ubiquitously display low levels of lysosomal ASM accompanied by high levels of lysosomal SM, thereby rendering their lysosomal membranes exceptionally fragile. Counterintuitively, studies in cell culture and published data indicated that diverse tumors actually display reduced SM content. Sequencing three pairs of vector- and c-src-transduced NIH 3T3 MEFs revealed the reduction of both ASM and neutral sphingomyelinase (NSM). Consistent with this observation, a search of public microarray databases revealed that human tumor tissues generically display reduced ASM and NSM. The authors conclude from these data that the primary event must be reduction in SM levels by an unknown mechanism, followed by secondary reduction in sphingomyelinases. It was proposed that this generic SM reduction compensated for the fragility of the expanded tumor lysosomal compartment chronically exposed to excess destructive hydrolases. This speculation must eventually be addressed experimentally. As a consequence of this unique biology, Petersen et al., 2013Petersen N.H.T. Olsen O.D. Groth-Pedersen L. Ellegard A.-M. Bilgin M. Redmer S. Ostenfeld M.S. Ulanet D. Dovmark T.H. Lønborg A. et al.Cancer Cell. 2013; 24 (this issue): 379-393Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar hypothesized that the low levels of lysosomal ASM might render tumor cells particularly sensitive to stoichiometric inactivation by CADs and subsequent LMP-induced tumor cell death. Studies using cells with multi-drug resistance (MDR) due to ABCB1 overexpression support the hypothesis that targeting lysosomal SM levels might represent a novel therapeutic strategy. Published data showed MDR improved by CADs, and, in 1995, Levade noted that this correlated with ASM inhibition (Jaffrézou et al., 1995Jaffrézou J.P. Chen G. Durán G.E. Muller C. Bordier C. Laurent G. Sikic B.I. Levade T. Biochim. Biophys. Acta. 1995; 1266: 1-8Crossref PubMed Scopus (56) Google Scholar). Because ABCB1 is a physiologic transporter of sphingolipids, it was not entirely surprising that MDR variants of the PC3 and DU145 prostate cancer lines displayed higher ASM levels and activity than the parental lines. What is exciting about the current publication is the observation that, in addition to siramesine antagonizing MDR, siRNA to SMPD1, the ASM gene, was as effective as siRNA to ABCB1 in reverting the MDR phenotype. The question of how to approach these new concepts clinically remains. Because CADs are well represented in the pharmacologic armamentarium, with millions of patients being prescribed tricyclic antidepressant, calcium channel blocker, and antihistamine CADs, it seems unlikely that a potent antitumor effect would have gone unnoticed. Perhaps a retrospective analysis will be revealing. Alternatively, perhaps the range of doses required for the diverse clinical applications of these drugs are insufficient for LMP, which would represent a toxicity of this drug class. Thus, it may be important to select CADs with potent LMP-inducing capabilities to take forward into the clinic. Ultimately, CAD drug scheduling, dosing, and combination with chemotherapeutics will have to be addressed if these concepts of SM-based LMP therapy are to be effectively tested clinically. Transformation-Associated Changes in Sphingolipid Metabolism Sensitize Cells to Lysosomal Cell Death Induced by Inhibitors of Acid SphingomyelinasePetersen et al.Cancer CellSeptember 09, 2013In BriefLysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome-destabilizing experimental anticancer agent siramesine inhibits ASM by interfering with the binding of ASM to its essential lysosomal cofactor, bis(monoacylglycero)phosphate. Like siramesine, several clinically relevant ASM inhibitors trigger cancer-specific lysosomal cell death, reduce tumor growth in vivo, and revert multidrug resistance. Full-Text PDF Open Archive" @default.
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• W1987672018 title "It Takes a CAD to Kill a Tumor Cell with a LMP" @default.
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