Ferroptosis in colorectal cancer: a future target?

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide and is characterised by frequently mutated genes, such as APC, TP53, KRAS and BRAF. The current treatment options of chemotherapy, radiation therapy and surgery are met with challenges such as cancer recurrence, drug resistance, and overt toxicity. CRC therapies exert their efficacy against cancer cells by activating biological pathways that contribute to various forms of regulated cell death (RCD). In 2012, ferroptosis was discovered as an iron-dependent and lipid peroxide-driven form of RCD. Recent studies suggest that therapies which target ferroptosis are promising treatment strategies for CRC. However, a greater understanding of the mechanisms of ferroptosis initiation, propagation, and resistance in CRC is needed. This review provides an overview of recent research in ferroptosis and its potential role as a therapeutic target in CRC. We also propose future research directions that could help to enhance our understanding of ferroptosis in CRC.

Fig. 1. The regulation and targeting of ferroptosis in CRC.

The following nodes are proposed as potential therapeutic targets for CRC: ① p53: p53 negatively regulates ferroptosis by inhibiting DPP4 in CRC cells. ② ACSL4: ACSL4 plays a crucial role in the induction of ferroptosis in KRAS mutant CRC. ③ GPX4: Several molecules have been reported to induce ferroptosis by targeting GPX4 in CRC. ④ SLC7A11: As a subunit of system xCT, inhibited can induce ferroptosis. ⑤ AA: AA metabolism might be a potential target in CRC. LOXs also oxidise AA at different carbon sites and regulate cellular redox homoeostasis. Evidence showed that LOXs are important regulatory mechanisms of ferroptosis and its inhibitors such as the vitamin E family (tocopherols and tocotrienols) are effective in preventing ferroptotic death. ACSL4 acyl coenzyme A synthetase long-chain family member 4, AA arachidonic acid, BH2 dihydrobiopterin, BH4 tetrahydrobiopterin, CoA coenzyme A, DHFR dihydrofolate reductase, DHCR7 7-dehydrocholesterol reductase, Fe iron, FSP1 ferroptosis suppressor protein 1, FPP farnesyl pyrophosphate, GSH glutathione, GSSG glutathione disulfide, GCH1 GTP cyclohydrolase-1, GCS glutamylcysteine synthetase, GLS glutaminase, GPX4 glutathione peroxidase 4, GPP geranyl pyrophosphate, HMG-CoA 3-hydroxy-3-methylglutaryl CoA, HETE hydroxyeicosatetraenoic acids, HPETE hydroperoxyeicosatetraenoic acid, IPP Isopentenyl pyrophosphate, LPCAT3 lysophosphatidylcholine acyltransferase 3, LPCAT lysophosphatidylcholine acyltransferase, LTA4 leukotriene A4, LTB4 leukotriene B4, LTC4 leukotriene C4, NRF2, nuclear factor E2-related factor 2; OOH, hydroperoxide; PE-PUFA, phosphatidylethanolamine polyunsaturated fatty acid, PUFA polyunsaturated fatty acid, PGD2 prostaglandin D2, PGE2 prostaglandin E2, PGF2α prostaglandin F2α, PGF2β prostaglandin F2β, SAM S-Adenosylmethionine, SAH S-Adenosylhomocysteine, TCA cycle tricarboxylic acid cycle, TFRC transferrin receptor, TSP pathway transsulfuration pathway, γ-GC γ-glutamylcysteine.

Fig. 2. Modulation of ferroptosis cancer cell immunity.

GPX4, ACSL4, LPCAT3 and LOXs (labelled (I)) mediate sensitivity to ferroptosis. ACSL4 is a key regulator of ferroptosis. It catalyzes the esterification of AA or AdA into PE, whereas LOXs can oxidise PE-AA and PE-AdA to PE-AA-OH and PE-AdA-OH (labelled (V)), further promoting ferroptosis. Ferroptosis can induce the attraction and activation of innate immune cells such as neutrophils, which are effectively engulfed by phagocytic cells. HMGB1 (labelled (II)), a damage-related molecular patterns (DAMP), has been shown to be released in response to ferroptosis [146]. It has been shown that in addition to PGE2 (labelled (III)), siderophiles also release 20-alkane compounds, such as 5-HETE, 12-HETE and 15-HETE (labelled (IV), in response to induction of GPX4 depletion [147]. ACSL4 acyl coenzyme A synthetase long-chain family member 4, AA arachidonic acid, AdA adrenic acid, CAF cancer-associated fibroblasts, CDC1 conventional type 1 dendritic cells, GPX4 glutathione peroxidase 4, HMGB1 high-mobility group box 1, LPCAT3 lysophosphatidylcholine acyltransferase 3, LOX Lipoxygenase, NK natural killer, oxPLs oxidised phospholipids, PE phosphatidylethanolamine, 5-HETE 5-hydroxy-eicosatrienoic acid, 12-HETE 12-hydroxy-eicosatrienoic acid, 15-HETE 15-hydroxy-eicosatrienoic acid, PTGS2 prostaglandin-endoperoxidase synthase 2, PGE2 prostaglandin E2, TAM tumour-associated macrophages, Treg cells regulatory T cell.