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

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Marcos Rios Garcia, Bettina Meissburger, Jessica Chan, Roldan M. de Guia, 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

Original languageEnglish
Article number2104291
JournalAdvanced Science
Volume9
Issue number29
DOIs
Accepted/In press2022
Published14 Oct 2022

Bibliographical note

Funding Information: This work was supported by a grant from the Else‐Kröner‐Fresenius‐Stiftung (Grant No. 2015_A240) and the Helmholtz Future Topic AmPro to S.H. and M.B.D. Support to M.L. included funding from the Xunta de Galicia (Grant No. 2016‐PG068); Ministerio de Economía y Competitividad (MINECO) co‐funded by the FEDER Program of EU (Grant No. RTI2018‐101840‐B‐I00); Atresmedia Corporación; “la Caixa” Foundation (ID 100010434), under the Grant Agreement No. LCF/PR/HR19/52160022. The authors thank Luke Harrison for proofreading the paper and for creating the Table of Contents figure, using Biorender.com. Publisher Copyright: © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.

King's Authors

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.

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