Stress response regulation of mRNA translation: Implications for antioxidant enzyme expression in cancer

Abstract

From tumorigenesis to advanced metastatic stages, tumor cells encounter stress, ranging from limited nutrient and oxygen supply within the tumor microenvironment to extrinsic and intrinsic oxidative stress. Thus, tumor cells seize regulatory pathways to rapidly adapt to distinct physiologic conditions to promote cellular survival, including manipulation of mRNA translation. While it is now well established that metastatic tumor cells must up-regulate their antioxidant capacity to effectively spread and that regulation of antioxidant enzymes is imperative to disease progression, relatively few studies have assessed how translation and the hijacking of RNA systems contribute to antioxidant responses of tumors. Here, we review the major stress signaling pathways involved in translational regulation and discuss how these are affected by oxidative stress to promote prosurvival changes that manipulate antioxidant enzyme expression. We describe how tumors elicit these adaptive responses and detail how stress-induced translation can be regulated by kinases, RNA-binding proteins, RNA species, and RNA modification systems. We also highlight opportunities for further studies focused on the role of mRNA translation and RNA systems in the regulation of antioxidant enzyme expression, which may be of particular importance in the context of metastatic progression and therapeutic resistance.

Keywords: Antioxidant; Cancer; RNA.

Fig. 1.

mTOR and the integrated stress response (ISR) regulate CAP-dependent translation. (A) During different stages of the tumor development and progression, cancer cells experience various forms of intrinsic and extrinsic sources of stress that activate (B) or inhibit mTOR-dependent protein synthesis (C), pathways that block high-energy-demanding cap-dependent translation and thus aid tumor cell survival. (B) Phosphorylation of eIF2α by ISR kinases PKR, HRI, PERK, and GNC2 results in the abrogation of translation initiation. (C) mTORC1 integrates growth factor and oncogene signaling inputs and adjusts mRNA translation based on cellular demands. (D) The cap-dependent translation machinery is regulated at the formation of the 43S preinitiation complex, translational initiation via eIF4, and elongation via eEF2.

Fig. 2.

IRES and uORFs drive selective, cap-independent translation. (A) i) Translation of two uORF within the 5′UTR of the ATF4 transcript inhibits ATF4 translation in normal conditions. ii) In response to the ISR, the level of functional eIF2 decreases, and the scanning ribosome cannot associate with the translation initiation factors in a timely fashion. Delayed translation reinitiation allows time for ribosome to scan through and bypass of the second uORF allowing for ATF4 protein synthesis initiation at the main ORF. (B) i) Under normal conditions, IRES elements can inhibit translation of stress response transcripts by structurally interfering binding of the ribosome with the ORF. ii) Under stress conditions, conformational changes in IRES elements can trigger translation in a cap-independent manner by directly recruiting the ribosome to the mRNA near the AUG start codon through interaction with ITAFs.

Fig. 3.

Regulatory changes to tRNA structure. Under low abundance of essential amino acids, tRNAs can no longer be charged with their corresponding amino acids, and this leads to accumulation of uncharged tRNAs, GCN2 activation, and translational reprogramming. tRNA modifications include cleavage, chemical modifications, and mischarging. Endonucleolytic cleavage of tRNAs can lead to 5′ and 3′ halves, and the 5′ half directly inhibits translation initiation. Cleavage at the 3′ end eliminates the CCA sequence and deactivates tRNAs to reduce the functional tRNA pool under stress. Among many chemical modifications in tRNAs, mcm⁵Um at the wobble U34 base is particularly important for selenocysteine incorporation. tRNA mischarging increases the frequency of Met misincorporation to nascent polypeptides, which in turn protects cells from oxidative stress through sulfur-dependent ROS scavenging.