Quantitative Proteomic Profiling Reveals Key Pathways in the Anticancer Action of Methoxychalcone Derivatives in Triple Negative Breast Cancer

Catherine C. Going, Dhanir Tailor, Vineet Kumar, Alisha M. Birk, Mallesh Pandrala, Meghan A. Rice, Tanya Stoyanova, Sanjay Malhotra, Sharon J. Pitteri

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Triple negative breast cancer is an aggressive, heterogeneous disease with high recurrence and metastasis rates even with modern chemotherapy regimens and thus is in need of new therapeutics. Here, three novel synthetic analogues of chalcones, plant-based molecules that have demonstrated potency against a wide variety of cancers, were investigated as potential therapeutics for triple negative breast cancer. These compounds exhibit IC50 values of ∼5 μM in triple negative breast cancer cell lines and are more potent against triple negative breast cancer cell lines than against nontumor breast cell lines according to viability experiments. Tandem mass tag-based quantitative proteomics followed by gene set enrichment analysis and validation experiments using flow cytometry, apoptosis, and Western blot assays revealed three different anticancer mechanisms for these compounds. First, the chalcone analogues induce the unfolded protein response followed by apoptosis. Second, increases in the abundances of MHC-I pathway proteins occurs, which would likely result in immune stimulation in an organism. And third, treatment with the chalcone analogues causes disruption of the cell cycle by interfering with microtubule structure and by inducing G1 phase arrest. These data demonstrate the potential of these novel chalcone derivatives as treatments for triple negative breast cancer, though further work evaluating their efficacy in vivo is needed.

Original languageEnglish (US)
Pages (from-to)3574-3585
Number of pages12
JournalJournal of Proteome Research
Volume17
Issue number10
DOIs
StatePublished - Oct 5 2018
Externally publishedYes

Keywords

  • chalcone
  • mechanism of action
  • tandem mass tag (TMT)
  • triple negative breast cancer
  • unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

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