Selenoproteins and tRNA-Sec: regulators of cancer redox homeostasis

Abstract

In the past two decades significant progress has been made in uncovering the biological function of selenium. Selenium, an essential trace element, is required for the biogenesis of selenocysteine which is then incorporated into selenoproteins. These selenoproteins have emerged as central regulators of cellular antioxidant capacity and maintenance of redox homeostasis. This review provides a comprehensive examination of the multifaceted functions of selenoproteins with a particular emphasis on their contributions to cellular antioxidant capacity. Additionally, we highlight the promising potential of targeting selenoproteins and the biogenesis of selenocysteine as avenues for therapeutic intervention in cancer. By understanding the intricate relationship between selenium, selenoproteins, and reactive oxygen species (ROS), insights can be gained to develop therapies that exploit the inherent vulnerabilities of cancer cells.

Keywords: ferroptosis; oxidative stress; reactive oxygen species; redox; selenium; selenoprotein.

Figure 1.. Relevance of human plasma selenium levels to human health.

A particular focus on key findings from selenium supplementation trials for cancer prevention. See [23,25,31,33,35,36,38,39].

Figure 2.. Conserved catalytic cycle of glutathione peroxidases.

Starting from (1), the catalytic selenocysteine exists in a base state as a selenol (Se⁻) which quickly reacts with hydrogen peroxide to generate (2) selenenic acid (SeOH), a temporary intermediate that is rapidly replaced by reduced glutathione (GSH) to form (3) a selenenyl sulfide adduct (SeSG). The enzyme is subsequently regenerated to (1) through its reaction with a second GSH, resulting in the production of oxidized glutathione (GSSG).

Figure 3.. Conserved biological mechanism of thioredoxin.

The thioredoxin pathway allows electrons from metabolism to cycle through the redox machinery, thereby maintaining a reduced cellular environment. From left to right, NADPH generated from the pentose phosphate metabolic pathway binds to a dimer of oxidized thioredoxin reductase (TrxR). Next, the TrxR dimer forms a yin-yang orientation where the “head” of protein 1 (1) binds into the “tail” of protein 2 (2) to reduce a Se-S bond mediated through an FAD cofactor. This process is performed in duplicate with the “tail” of (1) binding into the “head” of (2) (not shown). Third, the reduced TrxR dimer can then recycle oxidized thioredoxin by binding to the selenocysteine of the reduced TrxR. The resulting electron shuttle restores thioredoxin to its reduced form, thus regaining its cellular redox capabilities.

Figure 4.. Selenocysteine biosynthesis and post transcriptional modifications of tRNA-selenocysteine (tRNA^[Ser]Sec).

(A) Biogenesis of selenocysteine. tRNA-sec is initially aminoacylated with serine by seryl-tRNA synthetase (SARS). Phosphoseryl tRNA Kinase (PSTK) phosphorylates Ser-tRNA^[Ser]Sec , allowing for substitution of the oxygen for a selenium by selenophosphate synthetase 2 (SEPHS2) and (Sep (O-Phosphoserine) TRNA:Sec (Selenocysteine) TRNA Synthase) SEPSECS, forming selenocysteine on the tRNA. (B) Post transcriptional modifications of tRNA-sec. tRNA-sec contains four post transcriptional modifications, 1-methyladenosine (m¹A) 51 placed by the tRNA (adenine(58)-N(1))-methyltransferase non-catalytic subunit (TRM6) and TRNA (Adenine-N(1)-)-Methyltransferase Catalytic Subunit (TRM61), Pseudouridine (ψ) 55 placed by PseudoUridine Synthase 4 (PUS4), N6-isopentlyadenosine (i⁶A) placed by tRNA isopentyltransferase 1 (TRIT1), and 5-methoxycarbonylmethyl-(2’-O-methyl)-uridine (mcm⁵U(m)) placed in conjunction by the Elongator Complex (cm⁵), AlkB Homolog 8, tRNA methyltransferase (AlkBH8) (mcm⁵), and FtsJ RNA 2’-O-Methyltransferase 1 (FTSJ1) (Um). While mcm⁵ is essential for selenoprotein translation, the necessity for 2’-O-methylation is variable through poorly understood mechanisms.

Figure 5.. Key figure. Hazard ratios of selenoproteins across cancer types.

Unbiased hierarchal clustering was used for visualization of statistically significant (p<0.05) selenoprotein hazard ratios across various cancers with branches representing statistically similar groupings of genes or cancers. A hazard ratio of 1 indicates no difference between groups (high vs low expression of selected gene). Hazard ratios >1 (Blue) indicates correlation between higher expression and lower survival of the indicated gene. Hazard ratios <1 (Yellow) indicates correlation between lower expression and higher survival of the indicated gene. Hazard ratios with nonsignificant correlations (p>0.05) were not included in the analysis and are represented as gray boxes. Several cancers such as liver hepatocellular carcinoma, glioblastoma, and head-neck squamous cell carcinoma have multiple selenoprotein hazard ratios > 1 indicating that efforts to reduce selenoprotein expression may provide therapeutic benefit. Other cancers such as cervical squamous cell carcinoma and uterine corpus endometrial carcinoma have multiple selenoprotein hazard ratios < 1 indicating that efforts to boost selenoprotein expression may provide therapeutic benefit. However, throughout the analysis of 25 selenoproteins across 27 cancers the only cancer with a net positive or negative survival correlation with selenoprotein expression is glioblastoma. Furthermore, many selenoproteins have significant and opposite correlations with patient survival across different cancer types. This data highlights the complexity and context dependent role of selenoproteins across different cancer types.