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Cooperation effects of radiation and ferroptosis on tumor suppression and radiation injury - PubMed

  • ️Sat Jan 01 2022

Review

Cooperation effects of radiation and ferroptosis on tumor suppression and radiation injury

Jing Su et al. Front Cell Dev Biol. 2022.

Abstract

Ferroptosis is a kind of oxidative stress-dependent cell death characterized by iron accumulation and lipid peroxidation. It can work in conjunction with radiation to increase reactive oxygen species (ROS) generation and disrupt the antioxidant system, suppressing tumor progression. Radiation can induce ferroptosis by creating ROS, depleting glutathione, activating genes linked to DNA damage and increasing the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) in tumor cells. Furthermore, ferroptosis can enhance radiosensitivity by causing an iron overload, destruction of the antioxidant system, and lipid peroxidation. Radiation can also cause ferroptosis in normal cells, resulting in radiation injury. The role of ferroptosis in radiation-induced lung, intestinal, skin, and hematological injuries have been studied. In this review, we summarize the potential mechanisms linking ferroptosis, oxidative stress and radiation; analyze the function of ferroptosis in tumor suppression and radiation injury; and discuss the potential of ferroptosis regulation to improve radiotherapy efficacy and reduce adverse effects.

Keywords: GPX4; SLC7A11; ferroptosis; oxidative stress; radiotherapy; reactive oxygen species (ROS).

Copyright © 2022 Su, Bian, Zheng, Wang, Meng, Xin and Jiang.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

Regulatory pathways of ferroptosis. Ferroptosis is co-regulated by iron metabolism, lipid metabolism, and antioxidant systems. The inhibition of lipid peroxidation is mainly mediated by the SLC7A11-GSH-GPX4 pathway, FSP1-CoQ10-NAD (P)H pathway, GCH1-BH4-DHFR pathway and DHO-DHODH-OA pathway. Among them, the FSP1 pathway exists in the cytoplasm, the DHODH pathway exists in the mitochondria, and the GPX4 pathway plays a role in both. SLC7A11, Cystine/glutamate antiporter solute carrier family seven member 11; GPX4, glutathione peroxidase 4; GSH, glutathione; FSP1, ferroptosis suppressor protein 1; GGH1, GTP Cyclohydrolase 1; BH4, tetrahydrobiopterin; DHFR, dihydrofolate reductase; DHO, dehydrogenation of dihydroorotate; DHODH, Dihydroorotate Dehydrogenase; OA, orotate; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; ALOXs, arachidonate lipoxygenases; POR, cytochrome P450 oxidoreductase.

FIGURE 2
FIGURE 2

Mechanism of ferroptosis induced by radiotherapy. Radiation can inhibit the antioxidant function of SLC7A11 and GSH, and up-regulate the expression of ACSL4, thus inducing ferroptosis. However, radiation can aslo up-regulate the expression of SLC7A11 and GPX4 due to adaptive response. SLC7A11, Cystine/glutamate antiporter solute carrier family seven member 11; GPX4, glutathione peroxidase 4; GSH, glutathione; ACSL4, acyl-CoA synthetase long-chain family member 4.

FIGURE 3
FIGURE 3

Synthesis of plasmalogens. FAR1 is a key enzyme in the synthesis of plasmalogen. It can convert saturated fatty alcohols into unsaturated fatty. The TMEM189 gene encodes plasmanylethanolamine desaturase, which could introduce the vinyl ether double bond into plasmalogens and convert alkyl-ether lipids into plasmalogens. However, FAR1 is regulated by the negative feedback of phospholipid level, and it can be inhibited by an increase in plasmalogens content. FAR1, fatty acyl-CoA reductase 1; GNPAT, glyceronephosphate-O-acyltransferase; AGPS, alkylglycerone phosphate synthase.

FIGURE 4
FIGURE 4

PIEZO1 regulates radiation-induced ferroptosis in lung endothelial cells. Radiation increased the expression of PIEZO1 in the lung endothelial cells, which caused the influx of Ca2+. Increased intracellular Ca2+ activates caipain and promotes ferroptosis by regulating SLC7A11, GPX4, and DMT1 expression. Besides, the Ca2+/Caipain pathway can also promote the degradation of VE-cadherin, leading to ferroptosis. PIEZ O 1, Piezo-type mechanosensitive ion channel component 1; SLC7A11, Cystine/glutamate antiporter solute carrier family seven member 11; GPX4, glutathione peroxidase 4; DMT1, divalent metal transporter 1.

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