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.Significance: These findings highlight agents that target transcriptional addiction in cancer cells and suggest combination treatments that target RNA processing and DNA repair pathways simultaneously as effective cancer therapies.

• Authors: Sylvain Peuget, Jiawei Zhu, Gema Sanz, Madhurendra Singh, Massimiliano Gaetani, Xinsong Chen, Yao Shi, Amir Ata Saei, Torkild Visnes, Mikael S Lindström, Ali Rihani, Lidia Moyano-Galceran, Joseph W Carlson, Elisabet Hjerpe, Ulrika Joneborg, Kaisa Lehti, Johan Hartman, Thomas Helleday, Roman Zubarev, Galina Selivanova
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 7 Pg. 1538-1550 (04 01 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32019870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Flavonoids
• Furans
• Indoles
• NSC 652287
• Poly(ADP-ribose) Polymerase Inhibitors
• Proteome
• oncrasin-1
• aminoflavone

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Line, Tumor
• Female
• Flavonoids (pharmacology, therapeutic use)
• Furans (pharmacology, therapeutic use)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (pharmacology, therapeutic use)
• Oncogenes (genetics)
• Oxidative Stress (drug effects)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)
• Proteome (genetics)
• Proteomics (methods)
• Recombinational DNA Repair (drug effects)
• Signal Transduction (drug effects, genetics)
• Synthetic Lethal Mutations (drug effects)
• Transcription, Genetic (drug effects)