Identification of Cytoskeleton-Associated Proteins Essential for Lysosomal Stability and Survival of Human Cancer Cells
| العنوان: | Identification of Cytoskeleton-Associated Proteins Essential for Lysosomal Stability and Survival of Human Cancer Cells |
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| المؤلفون: | Elisabeth Corcelle-Termeau, Marja Jäättelä, Jesper Nylandsted, Nikolaj H.T. Petersen, Sonja Aits, Line Groth-Pedersen |
| المصدر: | PLoS ONE PLoS ONE, Vol 7, Iss 10, p e45381 (2012) |
| بيانات النشر: | Public Library of Science, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Small interfering RNA, Cell Membrane Permeability, lcsh:Medicine, Kinesins, Apoptosis, Tropomyosin, Biochemistry, HeLa, RNA interference, Drug Discovery, Molecular Cell Biology, RNA, Small Interfering, lcsh:Science, Protein Metabolism, Cellular Stress Responses, Multidisciplinary, biology, Cell Death, Cell biology, Oncology, Medicine, Membranes and Sorting, Female, Metabolic Pathways, medicine.drug, Research Article, Programmed cell death, Drugs and Devices, Breast Neoplasms, Myosins, Minor Histocompatibility Antigens, medicine, Genetics, Autophagy, Humans, Mitosis, Biology, Mannose 6-phosphate receptor, lcsh:R, Siramesine, Proteins, Thiones, biology.organism_classification, Cytoskeletal Proteins, Metabolism, Pyrimidines, Cancer cell, lcsh:Q, Gene expression, Lysosomes, HeLa Cells |
| الوصف: | Microtubule-disturbing drugs inhibit lysosomal trafficking and induce lysosomal membrane permeabilization followed by cathepsin-dependent cell death. To identify specific trafficking-related proteins that control cell survival and lysosomal stability, we screened a molecular motor siRNA library in human MCF7 breast cancer cells. SiRNAs targeting four kinesins (KIF11/Eg5, KIF20A, KIF21A, KIF25), myosin 1G (MYO1G), myosin heavy chain 1 (MYH1) and tropomyosin 2 (TPM2) were identified as effective inducers of non-apoptotic cell death. The cell death induced by KIF11, KIF21A, KIF25, MYH1 or TPM2 siRNAs was preceded by lysosomal membrane permeabilization, and all identified siRNAs induced several changes in the endo-lysosomal compartment, i.e. increased lysosomal volume (KIF11, KIF20A, KIF25, MYO1G, MYH1), increased cysteine cathepsin activity (KIF20A, KIF25), altered lysosomal localization (KIF25, MYH1, TPM2), increased dextran accumulation (KIF20A), or reduced autophagic flux (MYO1G, MYH1). Importantly, all seven siRNAs also killed human cervix cancer (HeLa) and osteosarcoma (U-2-OS) cells and sensitized cancer cells to other lysosome-destabilizing treatments, i.e. photo-oxidation, siramesine, etoposide or cisplatin. Similarly to KIF11 siRNA, the KIF11 inhibitor monastrol induced lysosomal membrane permeabilization and sensitized several cancer cell lines to siramesine. While KIF11 inhibitors are under clinical development as mitotic blockers, our data reveal a new function for KIF11 in controlling lysosomal stability and introduce six other molecular motors as putative cancer drug targets. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f1fd09e4c9799e5fa98ca5eb6bb4e990Test http://europepmc.org/articles/PMC3469574Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f1fd09e4c9799e5fa98ca5eb6bb4e990 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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