Y box binding protein 1 inhibition as a targeted therapy for ovarian cancer

Dhanir Tailor, Angel Resendez, Fernando Jose Garcia-Marques, Mallesh Pandrala, Catherine C. Going, Abel Bermudez, Vineet Kumar, Marjan Rafat, Dhanya K. Nambiar, Alexander Honkala, Quynh Thu Le, George W. Sledge, Edward Graves, Sharon J. Pitteri, Sanjay V. Malhotra

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Y box binding protein 1 (YB-1) is a multifunctional protein associated with tumor progression and the emergence of treatment resistance (TR). Here, we report an azopodophyllotoxin small molecule, SU056, that potently inhibits tumor growth and progression via YB-1 inhibition. This YB-1 inhibitor inhibits cell proliferation, resistance to apoptosis in ovarian cancer (OC) cells, and arrests in the G1 phase. Inhibitor treatment leads to enrichment of proteins associated with apoptosis and RNA degradation pathways while downregulating spliceosome pathway. In vivo, SU056 independently restrains OC progression and exerts a synergistic effect with paclitaxel to further reduce disease progression with no observable liver toxicity. Moreover, in vitro mechanistic studies showed delayed disease progression via inhibition of drug efflux and multidrug resistance 1, and significantly lower neurotoxicity as compared with etoposide. These data suggest that YB-1 inhibition may be an effective strategy to reduce OC progression, antagonize TR, and decrease patient mortality.

Original languageEnglish (US)
Pages (from-to)1206-1220.e6
JournalCell Chemical Biology
Volume28
Issue number8
DOIs
StatePublished - Aug 19 2021

Keywords

  • Y box binding protein 1
  • ovarian cancer
  • targeted therapy
  • treatment resistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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