PXD031110

PXD031110 is an original dataset announced via ProteomeXchange.

Title	PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-03-08
AnnouncementXML	Submission_2022-03-07_22:53:07.716.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dennis Kappei
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-20 09:04:58	ID requested
⏵ 1	2022-03-07 22:53:08	announced

Srinivas US, Tay NSC, Jaynes P, Anbuselvan A, Ramachandran GK, Wardyn JD, Hoppe MM, Hoang PM, Peng Y, Lim S, Lee MY, Peethala PC, An O, Shendre A, Tan BWQ, Jemimah S, Lakshmanan M, Hu L, Jakhar R, Sachaphibulkij K, Lim LHK, Pervaiz S, Crasta K, Yang H, Tan P, Liang C, Ho L, Khanchandani V, Kappei D, Yong WP, Tan DSP, Bordi M, Campello S, Tam WL, Frezza C, Jeyasekharan AD, PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production. Oncogene, 41(13):1986-2002(2022) [pubmed]

submitter keyword: ARID1A, PLK1, mitochondria, synthetic lethality, oxidative phosphorylation

Dennis Kappei
contact affiliation	Cancer Science Institute of Singapore, National University of Singapore
contact email	dennis.kappei@nus.edu.sg
lab head
Dennis Kappei
contact affiliation	Cancer Science Institute of Singapore
contact email	dennis.kappei@nus.edu.sg
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031110
     1. Label: PRIDE project
     2. Name: PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production