Cancer chemoprevention via activation of proteostatic modules. (28th January 2018)

• Record Type: Journal Article
• Authors: Sklirou, Aimilia; Papanagnou, Eleni-Dimitra; Fokialakis, Nikolas; Trougakos, Ioannis P.
• Is Part Of: Cancer letters. Volume 413(2018)
• Page Start: 110
• Page End: 121
• Publication Date: 2018-01-28
• Subjects: Cancer prevention -- Proteostasis network -- Natural products -- Nrf2 -- Chemopreventive agents; 6BIO 6-Bromoindirubin-3′-oxime -- ALP Autophagy Lysosome Pathway -- ARE antioxidant response elements -- ATF activating transcription factor -- DMBA 7, 12-dimethylbenz[a]anthracene -- ER Endoplasmic Reticulum -- FoxO forkhead box O -- Gsk-3 Glycogen synthase kinase-3 -- Hsf1 heat shock factor 1 -- Hsps heat shock proteins -- HSR heat shock response -- IRE1 inositol-requiring enzyme 1 -- Keap1 Kelch-like ECH-associated protein 1 -- NP natural product -- Nrf2 nuclear factor erythroid 2-related factor 2 -- OMMAD outer mitochondrial membrane associated degradation -- PEITC phenethyl isothiocyanate -- PERK protein kinase R-like endoplasmic reticulum kinase -- PKR protein kinase R -- PN Proteostasis Network -- PQC proteome quality control -- ROS Reactive Oxygen Species -- TPA 12-O-tetradecanoyl-phorbol-13-acetate -- UPR unfolded protein response -- UPRER endoplasmic reticulum unfolded protein response -- UPRMT mitochondrial unfolded protein response -- UPP Ubiquitin Proteasome Pathway -- XBP1 X box-binding protein; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.10.034
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Proteins carry out the majority of cellular functions and maintain cellular homeodynamics mostly by participating in multimeric assemblies that operate as protein machines. Proteome quality control is thus critical for cellular functionality, and it is carried out through the curating activity of the proteostasis network (PN). Key components of the PN are the protein synthesis and trafficking modules, the endoplasmic reticulum unfolded protein response, molecular chaperones, and the two main degradation machineries, namely the ubiquitin proteasome and autophagy lysosome pathways. Part of the PN are also several stress responsive pathways, including nuclear factor erythroid 2-related factor 2 (Nrf2), which mobilises genomic responses against oxidative and/or xenobiotic damage. Nevertheless, the gradual accumulation of stressors during ageing or earlier due to lifestyle results in an increasingly damaged and unstable proteome. This outcome may then increase genomic instability due to reduced DNA replication fidelity or repair, leading to various age-related diseases such as cancer. Considering that the activation of proteostatic modules exerts anti-ageing effects in model organisms, we present herein a synopsis of studies showing that proteostatic modules activation (e.g. by natural products) represents a promising tumour-chemopreventive approach. Highlights: Proteome stability is ensured by the highly integrated modular proteostasis network. Activation of proteostatic modules delays age-related proteome dysfunction. Increased proteotoxic stress and proteome instability is a hallmark of cancer. The issue of how loss-of-proteostasis affects tumour formation remains elusive. By activating proteostatic modules natural products promote cancer chemoprevention.