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Open Full Page Research Article Vincristine Induces Dramatic Lysosomal Changes and Sensitizes Cancer Cells to Lysosome-Destabilizing Siramesine Line Groth-Pedersen, Marie Stampe Ostenfeld, Maria Høyer-Hansen, Jesper Nylandsted, and Marja Ja¨a¨ttela¨ Apoptosis Department and Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark Abstract inhibited by the spindle assembly checkpoint (4, 5). Thus, it is not surprising that microtubule-targeting compounds that either Vincristine is a microtubule-destabilizing antimitotic drug that has been used in cancer therapy for over 40 years. destabilize (e.g., Vinca alkaloids) or stabilize (e.g., taxanes) the However, the knowledge on vincristine-induced cell death microtubule network are among the most effective anticancer pathways is still sparse. Here, we show that vincristine induces drugs that are commonly used in the treatment of leukemias and dramatic changes in the lysosomal compartment and sensi- lymphomas, as well as in the combination therapies of several tizes cells to lysosomal membrane permeabilization. In HeLa nonhematopoetic cancers (6, 7). cervix carcinoma cells, vincristine induced mitotic arrest and Vincristine, a naturally occurring Vinca alkaloid, destabilizes microtubules by binding to the Vinca domain in the h-tubulin massive cell death associated with an early increase in the subunit (8). Low concentrations of vincristine deprive the lysosomal volume and lysosomal leakage followed by the dynamicity of microtubules, whereas high concentrations lead to activation of the intrinsic apoptosis program. In contrast, a complete disassembly of the microtubule network (9). Conse- the majority of vincristine-treated MCF-7 breast carcinoma quently, no mitotic spindle can be formed, and cells are arrested in cells resisted apoptosis. Instead, they adapted to the spindle mitosis by spindle assembly checkpoint (4, 5). Peripheral neurop- assembly checkpoint and escaped the mitotic arrest as micro- athy is the main dose-limiting side effect of vincristine. It arises due nucleated and senescent cells with an increase in the volume to the breakdown of transport lines in axons followed by their and the activity of their lysosomal compartment. Consistent degeneration (10). As an attempt to develop chemotherapy with with its substantial effects on the lysosomes, vincristine greatly fewer side effects, several semisynthetic Vinca alkaloids with sensitized cultured cancer cells as well as orthotopic breast varying affinities to tubulin isoforms have been developed. One cancer xenografts in mice to the cytotoxicity induced by such compound is vinorelbine that binds axonal microtubules with siramesine, a sigma-2 receptor ligand that kills cancer cells by a weaker affinity than vincristine and therefore displays less destabilizing their lysosomes. Importantly, the combination neurotoxicity (6). Another strategy to avoid the neurotoxicity is to of nontoxic concentrations of vincristine and siramesine lower the dose of vincristine and combine it with other drugs. Due resulted in massive cell death even in MCF-7 cells that were to the limited knowledge of the cell death pathways initiated by capable of escaping vincristine-induced spindle assembly vincristine, the combination therapies used today may, however, be checkpoint and cell death. Similar synergism was observed far from optimal. when siramesine was combined with a semisynthetic vincris- Continuous treatment with microtubule poisons leads either to tine analogue, vinorelbine, or with microtubule-stabilizing an execution of a cell death pathway directly from the mitosis or paclitaxel. These data strongly suggest that combination to an escape from the mitotic arrest followed by cell division, therapies consisting of microtubule-disturbing and lysosome- senescence, or delayed cell death (4, 5). The mechanisms coupling destabilizing drugs may prove useful in the treatment of mitotic arrest to subsequent death remains almost completely otherwise therapy-resistant human cancers. [Cancer Res unexplored. Because the microtubule cytoskeleton has an impor- 2007;67(5):2217–25] tant role in the intracellular trafficking of organelles (e.g., endosomes, lysosomes, and autophagosomes), interference with Introduction its structure and dynamicity might also have lethal consequences The cytoskeleton of eukaryotic cells is composed of three major apart from those induced by the mitotic arrest. This hypothesis is protein families, intermediary filaments, actin filaments, and supported by the data showing that mitosis is not a prerequisite for microtubules that form filamentous structures throughout the the cytotoxicity of the microtubule-destabilizing drugs as shown by cell. The dynamic microtubule cytoskeleton consists of a- and the above-mentioned vincristine-induced toxicity in postmitotic h-tubulin dimers (1). It is responsible for the transport and neurons in vivo (6). Moreover, another microtubule-destabilizing positioning of intracellular organelles and the separation of drug, colchicine, induces cell death in cultured postmitotic chromatids during the anaphase of mitosis (2, 3). If the dynamicity cerebellar granule cells. In this case, the cell death is initiated by of the microtubule network is compromised, cell division is the depolymerization of the microtubule cytoskeleton followed by both caspase-dependent and caspase-independent cell death pathways (11). Thus, it is interesting to note that diminished Note: J. Nylandsted and M. Ja¨a¨ttela¨share the senior authorship. microtubule dynamicity induced by microtubule-stabilizing drugs Requests for reprints: Marja Ja¨a¨ttela¨, Apoptosis Department, Institute for Cancer induces leakage of lysosomal protease cathepsins into the cytosol Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, and cathepsin-mediated cell death in non–small cell lung cancer Denmark. Phone: 45-35257318; Fax: 45-35257721; E-mail: [email protected]. I2007 American Association for Cancer Research. cells (12). These data suggest that lysosomal integrity relies on the doi:10.1158/0008-5472.CAN-06-3520 undisturbed microtubule network, and the question arises whether www.aacrjournals.org 2217 Cancer Res 2007; 67: (5). March 1, 2007 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2007 American Association for Cancer Research. Cancer Research the lysosomal destabilization could be a more common conse- disturbing drugs with siramesine both in vitro and in vivo open new quence of microtubule-targeting drugs. exciting possibilities for cancer combination therapies. Apoptosis is the best defined cell death program counteracting tumor growth. It is characterized by the activation of a family of cysteine proteases called the caspases that trigger apoptosis- Materials and Methods associated morphologic changes such as the shrinkage of the cell, Cell culture and treatment. HeLa (human cervix carcinoma) cells were the condensation of the chromatin, and the disintegration of the kindly provided by J. Bartek (Danish Cancer Society, Copenhagen, cell into small fragments (13, 14). Most apoptosis pathways are Denmark). MCF-7 cell line used in this study is a subclone (MCF-7-S1) of initiated by the up-regulation or posttranslational modification of human ductal breast carcinoma cells originally selected for high sensitivity BH3-only proteins of the Bcl-2 family. They then activate to tumor necrosis factor (TNF; ref. 25). MCF-neo, MCF-vector, MCF-casp3, proapoptotic Bcl-2 family proteins Bax and Bak that induce the MCF-Beclin-2, and MCF-Beclin-15 cells are single-cell clones of MCF-7 cells mitochondrial outer membrane permeabilization and the release transfected with an empty vector or plasmids encoding for human caspase- 3 (pcDNA-casp3) or FLAG-Beclin 1 (pCR3.1-FLAG-Beclin 1; kindly of cytochrome c into the cytosol. Cytosolic cytochrome c facilitates provided by Beth Levine, Columbia University, New York, NY), respectively the assembly of the apoptosome, a multiprotein complex that (23, 26, 27). LC3-eGFP cells were created by transfecting MCF-7 cells with consists of Apaf-1, caspase-9, and cytochrome c, and serves as a pEGFP-C1 plasmid encoding for a fusion protein consisting of rat LC3 and scaffold to activate caspase-9, which then activates the so-called eGFP (kindly provided by G. Kroemer, CNRS-UMR8125, Villejuif, France) effector caspases (caspase-3 and caspase-7). Cancer cells frequently by electroporation followed by single-cell cloning by limiting dilution. The harbor acquired mutations that allow them to escape spontaneous cells were cultured in RPMI 1640with Glutamax (Life technologies, Ltd., and therapy-induced apoptosis (15, 16). For example, the up- Paisley, United Kingdom) supplemented with 6% heat-inactivated FCS regulation of antiapoptotic Bcl-2 family members and mutations in (biological industries, Kib. Beit, Haemek, Israel), 100 units/mL penicillin, the p53 tumor suppressor protein are common in human tumors. and 100 mg/mL streptomycin, and in the case of transfected cells also with A Apoptosis-resistant cancer cells are, however, not completely 400 g/mL geneticin sulfate (G-418; Invitrogen, Carlsbad, CA). The cells were maintained in a humidified atmosphere at 37jC, 5% CO and regularly resistant to cell death, but can die via alternative cell death 2 tested and found negative for Mycoplasma. pathways often involving non-caspase proteases such as lysosomal Siramesine was kindly provided by Christian Thomsen (H. Lundbeck A/S, cathepsins (17). Interestingly,
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