Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death
Abstract Aberrant energy metabolism and cell cycle regulation both critically contribute to malignant cell growth and both processes represent targets for anticancer therapy. It is shown here that depletion of the AAA+‐ATPase thyroid hormone receptor interacting protein 13 (Trip13) results in mitoti...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-10-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202104291 |
| _version_ | 1798019880756183040 |
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| author | Marcos Rios Garcia Bettina Meissburger Jessica Chan Roldan M. deGuia Frits Mattijssen Stephanie Roessler Andreas L. Birkenfeld Nathanael Raschzok Fabien Riols Janina Tokarz Maude Giroud Manuel Gil Lozano Goetz Hartleben Peter Nawroth Mark Haid Miguel López Stephan Herzig Mauricio Berriel Diaz |
| author_facet | Marcos Rios Garcia Bettina Meissburger Jessica Chan Roldan M. deGuia Frits Mattijssen Stephanie Roessler Andreas L. Birkenfeld Nathanael Raschzok Fabien Riols Janina Tokarz Maude Giroud Manuel Gil Lozano Goetz Hartleben Peter Nawroth Mark Haid Miguel López Stephan Herzig Mauricio Berriel Diaz |
| author_sort | Marcos Rios Garcia |
| collection | DOAJ |
| description | Abstract Aberrant energy metabolism and cell cycle regulation both critically contribute to malignant cell growth and both processes represent targets for anticancer therapy. It is shown here that depletion of the AAA+‐ATPase thyroid hormone receptor interacting protein 13 (Trip13) results in mitotic cell death through a combined mechanism linking lipid metabolism to aberrant mitosis. Diminished Trip13 levels in hepatocellular carcinoma cells result in insulin‐receptor‐/Akt‐pathway‐dependent accumulation of lipid droplets, which act as functional acentriolar microtubule organizing centers disturbing mitotic spindle polarity. Specifically, the lipid‐droplet‐coating protein perilipin 2 (Plin2) is required for multipolar spindle formation, induction of DNA damage, and mitotic cell death. Plin2 expression in different tumor cells confers susceptibility to cell death induced by Trip13 depletion as well as treatment with paclitaxel, a spindle‐interfering drug commonly used against different cancers. Thus, assessment of Plin2 levels enables the stratification of tumor responsiveness to mitosis‐targeting drugs, including clinically approved paclitaxel and Trip13 inhibitors currently under development. |
| first_indexed | 2024-04-11T16:48:04Z |
| format | Article |
| id | doaj.art-29dbd296ef80465abf81f709026d71f8 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-11T16:48:04Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-29dbd296ef80465abf81f709026d71f82022-12-22T04:13:30ZengWileyAdvanced Science2198-38442022-10-01929n/an/a10.1002/advs.202104291Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell DeathMarcos Rios Garcia0Bettina Meissburger1Jessica Chan2Roldan M. deGuia3Frits Mattijssen4Stephanie Roessler5Andreas L. Birkenfeld6Nathanael Raschzok7Fabien Riols8Janina Tokarz9Maude Giroud10Manuel Gil Lozano11Goetz Hartleben12Peter Nawroth13Mark Haid14Miguel López15Stephan Herzig16Mauricio Berriel Diaz17Institute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyJoint Division Molecular Metabolic Control DKFZ‐ZMBH Alliance and Network Aging Research German Cancer Research Center (DKFZ) 69120 Heidelberg GermanyInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyJoint Division Molecular Metabolic Control DKFZ‐ZMBH Alliance and Network Aging Research German Cancer Research Center (DKFZ) 69120 Heidelberg GermanyInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyInstitute of Pathology Liver Cancer Center Heidelberg (LCCH) University Hospital Heidelberg Im Neuenheimer Feld 224 69120 Heidelberg GermanyGerman Center for Diabetes Research (DZD) 85764 Neuherberg GermanyDepartment of Surgery Campus Charité Mitte and Campus Virchow‐Klinikum Charité‐Universitätsmedizin Berlin 2, Berlin Institute of Health (BIH) 10117 Berlin GermanyMetabolomics and Proteomics Core Helmholtz Center Munich 85764 Neuherberg GermanyInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyMetabolomics and Proteomics Core Helmholtz Center Munich 85764 Neuherberg GermanyNeurObesity Group Department of Physiology CIMUS University of Santiago de Compostela‐Instituto de Investigación Sanitaria Santiago de Compostela 15782 SpainInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyInstitute for Diabetes and Cancer Helmholtz Center Munich 85764 Neuherberg GermanyAbstract Aberrant energy metabolism and cell cycle regulation both critically contribute to malignant cell growth and both processes represent targets for anticancer therapy. It is shown here that depletion of the AAA+‐ATPase thyroid hormone receptor interacting protein 13 (Trip13) results in mitotic cell death through a combined mechanism linking lipid metabolism to aberrant mitosis. Diminished Trip13 levels in hepatocellular carcinoma cells result in insulin‐receptor‐/Akt‐pathway‐dependent accumulation of lipid droplets, which act as functional acentriolar microtubule organizing centers disturbing mitotic spindle polarity. Specifically, the lipid‐droplet‐coating protein perilipin 2 (Plin2) is required for multipolar spindle formation, induction of DNA damage, and mitotic cell death. Plin2 expression in different tumor cells confers susceptibility to cell death induced by Trip13 depletion as well as treatment with paclitaxel, a spindle‐interfering drug commonly used against different cancers. Thus, assessment of Plin2 levels enables the stratification of tumor responsiveness to mitosis‐targeting drugs, including clinically approved paclitaxel and Trip13 inhibitors currently under development.https://doi.org/10.1002/advs.202104291hepatocellular carcinomalipogenesismitosisMTOCsPlin2spindle assembly checkpoint |
| spellingShingle | Marcos Rios Garcia Bettina Meissburger Jessica Chan Roldan M. deGuia Frits Mattijssen Stephanie Roessler Andreas L. Birkenfeld Nathanael Raschzok Fabien Riols Janina Tokarz Maude Giroud Manuel Gil Lozano Goetz Hartleben Peter Nawroth Mark Haid Miguel López Stephan Herzig Mauricio Berriel Diaz Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death Advanced Science hepatocellular carcinoma lipogenesis mitosis MTOCs Plin2 spindle assembly checkpoint |
| title | Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death |
| title_full | Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death |
| title_fullStr | Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death |
| title_full_unstemmed | Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death |
| title_short | Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2‐Dependent Mitotic Cell Death |
| title_sort | trip13 depletion in liver cancer induces a lipogenic response contributing to plin2 dependent mitotic cell death |
| topic | hepatocellular carcinoma lipogenesis mitosis MTOCs Plin2 spindle assembly checkpoint |
| url | https://doi.org/10.1002/advs.202104291 |
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