2. Academic Validation
  3. Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2-Dependent Mitotic Cell Death

Trip13 Depletion in Liver Cancer Induces a Lipogenic Response Contributing to Plin2-Dependent Mitotic Cell Death

  • Adv Sci (Weinh). 2022 Oct;9(29):e2104291. doi: 10.1002/advs.202104291.
Marcos Rios Garcia 1 2 3 4,  Bettina Meissburger 5,  Jessica Chan 1 2 3,  Roldan M de Guia 5,  Frits Mattijssen 1 2 3,  Stephanie Roessler 6,  Andreas L Birkenfeld 3 7 8,  Nathanael Raschzok 9,  Fabien Riols 10,  Janina Tokarz 1 2 3,  Maude Giroud 1 2 3,  Manuel Gil Lozano 1 2 3,  Goetz Hartleben 1 2 3,  Peter Nawroth 1 2 3 11,  Mark Haid 10,  Miguel López 4 12,  Stephan Herzig 1 2 3 13,  Mauricio Berriel Diaz 1 2 3
Affiliations

Affiliations

  • 1 Institute for Diabetes and Cancer, Helmholtz Center Munich, 85764, Neuherberg, Germany.
  • 2 Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, University Hospital, 69120, Heidelberg, Germany.
  • 3 German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany.
  • 4 NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain.
  • 5 Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • 6 Institute of Pathology, Liver Cancer Center Heidelberg (LCCH), University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
  • 7 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, 72076, Tübingen, Germany.
  • 8 Department of Diabetes, School of Life Course Science, King's College London, London, WC2R 2LS, UK.
  • 9 Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin 2, Berlin Institute of Health (BIH), 10117, Berlin, Germany.
  • 10 Metabolomics and Proteomics Core, Helmholtz Center Munich, 85764, Neuherberg, Germany.
  • 11 Department of Medicine 1 and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
  • 12 CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Santiago de Compostela, 15706, Spain.
  • 13 Chair Molecular Metabolic Control, Technical University Munich, Germany.
PMID: 36031387 DOI: 10.1002/advs.202104291
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.

Keywords

MTOCs; Plin2; Trip13; hepatocellular carcinoma; lipogenesis; mitosis; spindle assembly checkpoint.

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