Proteomic Analysis Reveals Low-Dose PARP Inhibitor-Induced Differential Protein Expression in BRCA1-Mutated High-Grade Serous Ovarian Cancer Cells

Jesenia M. Perez, Carly A.I. Twigg, Weihua Guan, Stefani N. Thomas

Research output: Contribution to journalArticlepeer-review

Abstract

High-grade serous ovarian cancer (HGSOC) is the most common form of ovarian cancer diagnosed in patients worldwide. Patients with BRCA1/2-mutated HGSOC have benefited from targeted treatments such as poly(ADP-ribose) polymerase inhibitors (PARPi). Despite the initial success of PARPi-based ovarian cancer treatment regimens, approximately 70% of patients with ovarian cancer relapse and the 5-year survival rate remains at 30%. PARPi exhibit variable treatment efficacy and toxicity profiles. Furthermore, the off-target effects of PARP inhibition have not yet been fully elucidated, warranting further study of these classes of molecules in the context of HGSOC treatment. Highly reproducible quantitative mass spectrometry-based proteomic workflows have been developed for the analysis of tumor tissues and cell lines. To detect the off-target effects of PARP inhibition, we conducted a quantitative mass spectrometry-based proteomic analysis of a BRCA1-mutated HGSOC cell line treated with low doses of two PARPi, niraparib and rucaparib. Our goal was to identify PARPi-induced protein signaling pathway alterations toward a more comprehensive elucidation of the mechanism of action of PARPi beyond the DNA damage response pathway. A significant enrichment of nuclear and nucleoplasm proteins that are involved in protein binding was observed in the rucaparib-treated cells. Shared upregulated proteins between niraparib and rucaparib treatment demonstrated RNA II pol promoter-associated pathway enrichment in transcription regulation. Pathway enrichment analyses also revealed off-target effects in the Golgi apparatus and the ER. The results from our mass spectrometry-based proteomic analysis highlights notable off-target effects produced by low-dose treatment of BRCA1-mutated HGSOC cells treated with rucaparib or niraparib.

Original languageEnglish (US)
Pages (from-to)242-250
Number of pages9
JournalJournal of the American Society for Mass Spectrometry
Volume33
Issue number2
DOIs
StatePublished - Feb 2 2022
Externally publishedYes

Bibliographical note

Funding Information:
Mass spectrometry data were acquired in the Analytical Biochemistry Shared Resource of the University of Minnesota Masonic Cancer Center, supported in part by the National Cancer Institute (Cancer Center Support Grant No. CA-77598). S.N.T. acknowledges funding from the National Institutes of Health’s National Center for Advancing Translational Sciences, Grant No. UL1TR002494, via the University of Minnesota’s Clinical and Translational Science Institute. S.N.T. also acknowledges funding from the V Foundation from Cancer Research and startup funds provided by the University of Minnesota Department of Laboratory Medicine and Pathology.

Publisher Copyright:
© 2022 American Chemical Society.

Keywords

  • PARP inhibitor (PARPi)
  • mass spectrometry
  • ovarian cancer
  • proteomics
  • tandem mass tags (TMT)

PubMed: MeSH publication types

  • Journal Article

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