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Thermal proteome profiling identifies oxidative-dependent inhibition of the transcription of major oncogenes as a new therapeutic mechanism for select anticancer compounds

Abstract

Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis, and transcriptomics to identify a common MoA for the anticancer compounds RITA, aminoflavone (AF), and oncrasin-1 (Onc-1). Global thermal proteome profiling revealed that the three compounds target mRNA processing and transcription, thereby attacking a cancer vulnerability, transcriptional addiction. This led to the preferential loss of expression of oncogenes involved in PDGF, EGFR, VEGF, insulin/IGF/MAPKK, FGF, Hedgehog, TGFβ, and PI3K signaling pathways. Increased reactive oxygen species level in cancer cells was a prerequisite for targeting the mRNA transcription machinery, thus conferring cancer selectivity to these compounds. Furthermore, DNA repair factors involved in homologous recombination were among the most prominently repressed proteins. In cancer patient samples, RITA, AF, and Onc-1 sensitized to poly(ADP-ribose) polymerase inhibitors both in vitro and ex vivo. These findings might pave a way for new synthetic lethal combination therapies.
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Category

Academic article

Language

English

Author(s)

  • Sylvain Peuget
  • J Zhu
  • Gema Sanz
  • Madhurendra Singh
  • Massimiliano Gaetani
  • Xinsong Chen
  • Yao Shi
  • Amir Ata Saei
  • Torkild Visnes
  • Mikael Lindström
  • A Rihani
  • Lidia Moyano-Galceran
  • Joseph W. Carlson
  • Elisabeth Hjerpe
  • Ulrika Joneborg
  • Kaisa Lehti
  • Johan Hartman
  • Thomas Helleday
  • Roman A. Zubarev
  • Galina Selivanova

Affiliation

  • SINTEF Industry / Biotechnology and Nanomedicine
  • Karolinska Institutet
  • University of Sheffield

Year

2020

Published in

Cancer Research

ISSN

0008-5472

Volume

80

Issue

7

View this publication at Norwegian Research Information Repository