Selenium and the 15kDa Selenoprotein Impact Colorectal Tumorigenesis by Modulating Intestinal Barrier Integrity

Canter, Jessica A.; Ernst, Sarah E.; Peters, Kristin; Carlson, Bradley A.; Thielman, Noelle R J; Grysczyk, Lara; Udofe, Precious; Yu, Yunkai; Cao, Liang; Davis, Cindy D.; Gladyshev, Vadim N.; Hatfield, Dolph L.; Tsuji, Petra A.

doi:10.3390/ijms221910651

Cited by 20 publications

(12 citation statements)

References 67 publications

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“…Among our genes of interest, two selenoproteins were missing in the Cancer Dependency Map dataset, SELENOF and TXNRD3; thus, these could not be analyzed here. Although this is a limitation of this bioinformatics approach, the functions of SELENOF and TXNRD3 and their roles in disease have been experimentally analyzed recently by our group and others [ 12 , 13 , 14 , 15 ].…”

Section: Methodsmentioning

confidence: 99%

Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6

Santesmasses

Gladyshev

2022

Biomolecules

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The human genome has 25 genes coding for selenocysteine (Sec)-containing proteins, whose synthesis is supported by specialized Sec machinery proteins. Here, we carried out an analysis of the co-essentiality network to identify functional partners of selenoproteins and Sec machinery. One outstanding cluster included all seven known Sec machinery proteins and two critical selenoproteins, GPX4 and TXNRD1. Additionally, these nine genes were further positively associated with PRDX6 and negatively with SCD, linking the latter two genes to the essential role of selenium. We analyzed the essentiality scores of gene knockouts in this cluster across one thousand cancer cell lines and found that Sec metabolism genes are strongly selective for a subset of primary tissues, suggesting that certain cancer cell lineages are particularly dependent on selenium. A separate outstanding cluster included selenophosphate synthetase SEPHS1, which was linked to a group of transcription factors, whereas the remaining selenoproteins were linked neither to these clusters nor among themselves. The data suggest that key components of Sec machinery have already been identified and that their primary role is to support the functions of GPX4 and TXNRD1, with further functional links to PRDX6 and SCD.

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Section: Methodsmentioning

confidence: 99%

Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6

Santesmasses

Gladyshev

2022

Biomolecules

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“…Most selenoproteins have had their molecular function or regulatory role in cancer cell-related processes discussed elsewhere [ 123 ] with a few of them remaining understudied. Notably, the molecular mechanism of SELENOF and SELENOP in colorectal cancer development have been detailed using transgenic mouse models that lacked these enzymes [ 138 , 145 ]. Nevertheless, even accounting the many unknowns, the broad diversity of roles that this group of proteins display and the nature of their role in cancer cell according to developmental stage, genotypical variation, and prognostic and diagnostic value suggest a highly regulated fine tuning for selenoprotein synthesis in general.…”

Section: Impact Of Selenoproteins On Cancermentioning

confidence: 99%

Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers

et al. 2022

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A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis.

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“…SELENOF may be involved in the regulation of protein folding, and its deletion promotes nuclear cataracts in mice [ 102 ]. Several studies examined its possible role in cancer [ 103 , 104 ]. Altered expression, both high and low, has been linked to a higher cancer risk in different tissues, including lung, breast, prostate, and liver [ 105 ].…”

Section: Selenoproteinsmentioning

confidence: 99%

Historical Roles of Selenium and Selenoproteins in Health and Development: The Good, the Bad and the Ugly

Tsuji

Santesmasses

Lee

et al. 2021

IJMS

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Selenium is a fascinating element that has a long history, most of which documents it as a deleterious element to health. In more recent years, selenium has been found to be an essential element in the diet of humans, all other mammals, and many other life forms. It has many health benefits that include, for example, roles in preventing heart disease and certain forms of cancer, slowing AIDS progression in HIV patients, supporting male reproduction, inhibiting viral expression, and boosting the immune system, and it also plays essential roles in mammalian development. Elucidating the molecular biology of selenium over the past 40 years generated an entirely new field of science which encompassed the many novel features of selenium. These features were (1) how this element makes its way into protein as the 21st amino acid in the genetic code, selenocysteine (Sec); (2) the vast amount of machinery dedicated to synthesizing Sec uniquely on its tRNA; (3) the incorporation of Sec into protein; and (4) the roles of the resulting Sec-containing proteins (selenoproteins) in health and development. One of the research areas receiving the most attention regarding selenium in health has been its role in cancer prevention, but further research has also exposed the role of this element as a facilitator of various maladies, including cancer.

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Selenium and the 15kDa Selenoprotein Impact Colorectal Tumorigenesis by Modulating Intestinal Barrier Integrity

Cited by 20 publications

References 67 publications

Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6

Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6

Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers

Historical Roles of Selenium and Selenoproteins in Health and Development: The Good, the Bad and the Ugly

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