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PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Oncogene volume 41, pages 1986–2002 (2022)Cite this article

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A Correction to this article was published on 06 May 2022

This article has been updated

Abstract

Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2/M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.

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Fig. 1: ARID1A loss confers sensitivity to PLK1 inhibitors.
Fig. 2: A genome-wide CRISPR screen reveals that the mitochondrial translation network is a critical determinant of Volasertib-induced cell death in ARID1A KO cells.
Fig. 3: ARID1A KO cells have a grossly abnormal mitochondrial phenotype.
Fig. 4: ARID1A KO cells have abnormal mitochondrial function.
Fig. 5: PLK1 localizes to the mitochondria.
Fig. 6: PLK1 inhibition differentially affects the mitochondria of ARID1A KO cells.
Fig. 7: Mitochondrial translation components are critical to the sensitivity of ARID1A deficient cells to PLK1 inhibition.
Fig. 8: A potential clinical assay for broad evaluation of ARID1A loss in cancer.

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Data availability

The RNA seq and CRISPR screen data from this publication have been deposited to the Gene Expression Omnibus database [58] (https://www.ncbi.nlm.nih.gov/geo/) and assigned the identifier GSE193942. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [59] partner repository with the dataset identifier PXD031110.

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Acknowledgements

We would like to thank Dr Chen Gao Bin and Prof. Li Shang at the Duke-NUS CRISPR Core Facility for their assistance with the CRISPR screen.

Funding

ADJ is supported by the Singapore Ministry of Health’s National Medical Research Council Transition Award (NMRC/TA/0052/2016). Work in ADJ’s and the Kappei laboratory is also funded by the Cancer Science Institute of Singapore, National University of Singapore, through the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative. Part of this work was funded through a collaborative grant between ADJ and DSPT from the Singapore Ministry of Health’s National Medical Research Council (NMRC/CIRG/1400/2014). This research was also funded by the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2018-T2-2-179) to Karen Crasta.

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Author notes

  1. These authors Jointly Supervised this work: Upadhyayula S. Srinivas, Tay S.C. Norbert, Patrick Jaynes.

Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore (NUS), Singapore, Singapore

    Upadhyayula S. Srinivas, Norbert S. C. Tay, Patrick Jaynes, Akshaya Anbuselvan, Gokula K. Ramachandran, Joanna D. Wardyn, Michal M. Hoppe, Phuong Mai Hoang, Yanfen Peng, Sherlly Lim, Praveen C. Peethala, Omer An, Akshay Shendre, Bryce W. Q. Tan, Sherlyn Jemimah, Henry Yang, Vartika Khanchandani, Dennis Kappei, Wei Peng Yong, David S. P. Tan, Wai Leong Tam & Anand D. Jeyasekharan

  2. Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), Singapore, Singapore

    May Yin Lee, Patrick Tan & Wai Leong Tam

  3. Institute of Molecular and Cell Biology (IMCB), Agency for Science Technology and Research (A*STAR), Singapore, Singapore

    Manikandan Lakshmanan

  4. Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

    Longyu Hu & Patrick Tan

  5. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore

    Rekha Jakhar, Karishma Sachaphibulkij, Lina H. K. Lim, Shazib Pervaiz & Karen Crasta

  6. Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore

    Rekha Jakhar & Karen Crasta

  7. Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore

    Chao Liang & Lena Ho

  8. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore

    Dennis Kappei & Wai Leong Tam

  9. NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore

    Dennis Kappei & Anand D. Jeyasekharan

  10. National University Cancer Institute, Singapore (NCIS), National University Hospital (NUH), Singapore, Singapore

    Wei Peng Yong, David S. P. Tan & Anand D. Jeyasekharan

  11. Department of Biology, University of Rome ‘Tor Vergata’, Rome, Italy

    Matteo Bordi & Silvia Campello

  12. MRC Cancer Unit, University of Cambridge, Cambridge, UK

    Christian Frezza

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  1. Upadhyayula S. Srinivas
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Contributions

Conceptualization: USS, PJ, ADJ. Data curation: USS, OA, AS, HY. Formal analysis: USS, SL, MMH, SJ, VK. Funding acquisition: ADJ. Investigation: USS, TSCN, AA, GKR, JDW, MYL, PCP, BWQT, LHu, RJ, KS, MB, YP, SL, LC, PMH. Methodology: USS, DK, SC, WLT, CF, ADJ. Project administration: ADJ. Resources: LHKL, ML, SP, KC, PT, DK, YWP, CF, DSPT, WLT, LHo, SC, ADJ. Software – OA, HY. Supervision: ADJ, PJ. Validation: USS, TSCN, AA, PJ, LHKL, SP, KC, PT, DK, YWP, CF, DSPT, WLT, AS, HY, OA. Visualization: USS, MMH, TSCN, PJ, ADJ. Writing – original draft – USS, PJ, ADJ. Writing – review and editing - LHKL, SP, KC, PT, DK, YWP, CF, DSPT, WLT, PJ, ADJ.

Corresponding author

Correspondence to Anand D. Jeyasekharan.

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Competing interests

ADJ: honoraria from Turbine Ltd, AstraZeneca, Antengene, Janssen and MSD, travel funding from Perkin Elmer, and research funding from Janssen and AstraZeneca. DSPT: honoraria from AstraZeneca, Roche, Bayer, MSD, Merck Serono, Tessa Therapeutics, Novartis, and Genmab and research funding from AstraZeneca, Bayer and Karyopharm. The other co-authors have no conflicts of interest to declare.

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Srinivas, U.S., Tay, N.S.C., Jaynes, P. et al. PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production. Oncogene 41, 1986–2002 (2022). https://doi.org/10.1038/s41388-022-02219-8

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