Advances in ferroptosis of cancer therapy

Ying Dong; Chaojie Xu; Jinli Guo; Yuchen Liu

doi:10.1515/oncologie-2023-0513

Article Open Access

Advances in ferroptosis of cancer therapy

Ying Dong , Chaojie Xu , Jinli Guo and Yuchen Liu

Published/Copyright: January 1, 2024

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From the journal Oncologie Volume 26 Issue 1

Abstract

Ferroptosis is an iron-dependent mode of programmed cell death characterized by Reactive Oxygen Species (ROS) accumulation lipid peroxidation and glutathione depletion. It is a novel form of cell death different from apoptosis and necrosis. Because of its unique mode of cell death, it has attracted a large number of research reports from the oncology community. Changes in iron ions and accumulation of lipid peroxides have confirmed the correlation between ferroptosis and tumors, and thus ferroptosis can be considered to have a great oncological therapeutic potential. This paper brings to light the significance of metabolic pathways and key genes like System Xc-/Glutathione Peroxidase 4 (GPX4), Membrane-bound O-acyltransferases 1 (MBOAT1) and Membrane-bound O-acyltransferases 2 (MBOAT2) in modulating ferroptosis in cancer cells. The susceptibility of cancer cells to ferroptosis, influenced by their high levels of reactive oxygen species and specific mutation profiles, is analyzed, suggesting new avenues for enhancing the effectiveness of established cancer treatments. In this review, we address the current understanding of ferroptosis induction and ferroptosis defense mechanisms, briefly describe the role and mechanisms of ferroptosis in tumor suppression, and discuss therapeutic strategies for targeting ferroptosis caused by tumors.

Keywords: ferroptosis; cancer therapy; System Xc-/GPX4 pathway; MBOAT1 and MBOAT2

Introduction

Ferroptosis, a novel form of programmed cell death proposed by Dr. Brent R. Stockwell in 2012 [1], is distinct from apoptosis, necrosis, and autophagy in terms of its hallmark features and biological assays [2], [3], [4], [5] (Table 1). Ferroptosis, as the name implies, is related to the metabolism of iron ions, which are normally metabolized in the human body through the process of iron absorption, storage, transport, and utilization. And iron metabolism is a complex biochemical process that is critical to human health. Iron homeostasis is tightly regulated to ensure an adequate supply of iron for various physiological functions in the body, and once this homeostasis is lost, cells undergo abnormal changes [6], [7], [8]. Cells undergo ferroptosis essentially by intracellular Reactive Oxygen Species (ROS) accumulation, activation of the mitogen-activated protein kinase (MAPK) system [9], reduction of cystine uptake, depletion of intracellular glutathione (GSH), inhibition of the cystine/glutamate reverse transporter protein System Xc-{consisting of two subunits, the light chain subunit SLC7A11 (xCT) and the heavy chain subunit SLC3A2 (CD98)} and increase NADPH oxidases (NOXs), release mediators such as arachidonic acid (ARA), leading to oxidation of lipids by iron ions to produce ROS, which can induce cell death at a certain level [10]. The ultramorphological features of cells with ferroptosis showed cell membrane rupture and vesiculation, smaller mitochondria, increased membrane density, decreased or disappeared mitochondrial cristae, rupture of the outer mitochondrial membrane, and normal-sized nuclei but lack of chromatin condensation [11]. Electron microscopy showed small intracellular mitochondria and increased density of bilayer membranes. Cells that undergo ferroptosis immunologically release damage-associated molecular patterns (DAMPs) that promote inflammatory responses [12].

Table 1:

Comparison of characteristics of ferroptosis, apoptosis, and autophagy.

	Ferroptosis	Apoptosis	Autophagy
Functionality	Iron-dependent, accelerated cell membrane lipid peroxidation [1]	Orderly removal of aged, damaged or useless cells [2]	Break down and recycle useless cellular components such as organelles and proteins [3]
Biological indicators	ROS, lipid peroxides increase; GSH decrease; ROS, PTGS2 increase; NADPH decrease [4]	Cytochrome C release; caspase activation	Conversion of LC3-I to LC3-II
Influenced areas	Amino acid, iron ion metabolism	Embryonic development, tumor suppression, immune regulation	Stress, resistance to infection, maintenance of intracellular homeostasis
Hallmark	Mitochondrial cristae reduced (disappeared); outer mitochondrial membrane ruptured and crumpled; mitochondria darkly stained in color [5]	Chromatin condensation and breakage; loss of nucleoli; nuclear consolidation and fragmentation; autophagosome formation [5]	Autophagic lysosome formation [5]

Ferroptosis is not only dependent on iron driven by phospholipid peroxidation and influenced by multiple cellular metabolic pathways [10] (including redox homeostasis and coenzyme Q10 biosynthesis, mitochondrial activity, amino acid, lipid, and glucose metabolism) it is also regulated by a variety of signaling pathways related to diseases (e.g., Alzheimer’s disease [13], Huntington’s chorea, Parkinson’s syndrome [14], and tumors, etc.). As a unique cell death mechanism, ferroptosis may provide new opportunities for tumor treatment as a novel targeting target. In recent years, a large number of reports have shown that ferroptosis has made substantial progress in the treatment of tumors. Not only have a variety of tumor-associated signaling pathways (System Xc-/GPX4 pathway [15] and lipid metabolism pathway [7], etc.) been demonstrated to control ferroptosis in tumor cells, but also a variety of tumor suppressors involved in ferroptosis have been identified [16]. The high ROS load and specific mutational characteristics of tumor cells compared to normal cells make them inherently more susceptible to ferroptosis [17], thus making them more potential for targeted therapy. At the same time, some tumor cells survive conditions of cellular oxidative stress with the help of a ferroptosis resistance system [18]; thus, destabilization of the ferroptosis-defense system can lead to tumor cell death.

The emergence of ferroptosis has affected various fields of life sciences, especially in human tumors with great potential. Targeted regulation of ferroptosis-related genes can, to a certain extent, make up for the shortcomings of radiotherapy, chemotherapy and immunotherapy, which are too broad-spectrum, and take advantage of the characteristics of tumor cells that have a higher iron demand to maximize the elimination of tumor cells under the condition of minimizing the damage to normal cells. In this paper, a brief review of the current research findings on ferroptosis in tumor therapy is presented.

Mechanisms and key genes involved in the onset of ferroptosis in tumor cells

Excess accumulation of iron ions and lipid peroxidation are two key signals that trigger membrane oxidative damage during apoptosis [19]. The central molecular mechanism of ferroptosis involves a balance between oxidative damage and antioxidant defenses, and influencing the mechanism by which it occurs or its key genes can indirectly and/or directly sexually affect programmed cell death [20].

System Xc-/GPX4 pathway

GPX4, a key regulator of cellular ferroptosis, is the main enzyme that catalyzes the reduction of phospholipid hydroperoxides (PLOOH) in mammalian cells. GPX4 converts glutathione (GSH) to oxidized glutathione (GSSG) and reduces cytotoxic lipid peroxides (PL-OOH) to their corresponding alcohols (PL-OH), i.e., it attenuates the toxicity of lipid peroxides and maintains membrane lipid bilayer homeostasis, thereby inhibiting ferroptosis [21]. If GPX4 is inhibited, it leads to the accumulation of intracellular peroxides, which in turn triggers iron death (Figure 1) [22]. Li et al. [19] found that GPX4 is a central regulator of iron death by siRNA knockdown of GPX4, and that the reduction of GPX4 expression markedly promotes the accumulation of ROS in the cells and promotes the onset of cell death, consistent with the inhibition of System Xc-system, GPX4 is a key hub gene on this pathway [23]. Dihydroorotate dehydrogenase (DHODH) is a mitochondrial endomembrane enzyme that catalyzes pyrimidine ribonucleotide synthesis [24]. DHODH has been found to act in parallel with GPX4, but independently of cytoplasmic GPX4, in regulating mitochondrial ferroptosis, and can affect GPX4 by reducing ubiquinone to ubiquinol, which can be used to inhibit tumors, either alone in cancers with low GPX4 or in combination with iron oxidation inducers in cancers with high GPX4 effects [25].

Figure 1:

Signaling pathway of System Xc-.

The cystine/glutamate reverse transporter is an important intracellular antioxidant system, consisting of two subunits, SLC7A11 and SLC3A2L [26], which can take up cystine to reduce it to cysteine to synthesize glutathione and expel glutamate to the outside of the cell, glutathione can reduce reactive oxygen species by the action of glutathione peroxidase, thus decreasing glutathione synthesis, which can cause cellular oxidative damage and even ferroptosis in cells [27]. Polewski’s [28] team found that up-regulation of SL7A11 did not affect cell proliferation but increased anchorage-independent cell growth in glioblastoma. Knockdown of SLC7A11 increased basal reactive oxygen ROS and decreased glutathione production, a change that increased cell death in response to oxidative and genotoxic stress [29]. This finding confirms that affecting the System Xc-system, can lead to a redox imbalance in glioblastoma and inhibit tumor cell viability. Also in the experiments of de Souza et al. [30], it was confirmed that in gliomas, inhibition of System Xc-, leads to a rapid depletion of glutathione, which results in the loss of defense of tumor cells against ROS, increases cell death, and leads to apoptosis mediated by caspases, which suggests that inhibition of glioma cell uptake of cystine uptake may be a feasible way to eliminate tumor cells. In conclusion, based on the currently known experiments, it is known that cancer cells are able to establish better survival conditions for themselves by promoting the expression and function of the System Xc-/GPX4 system, which causes massive tumor progression.

AMPK signaling pathway

In experiments to protect the kidney from ischemia-reperfusion injury, it has been found that when cells are deprived of glucose, AMPK is activated, initiating an energetic stress-protection program used to counteract reactive oxygen species produced by starved cells as a result of metabolic stress, thereby protecting the cells from ferroptosis [31]. At this time, the mitochondria is predominantly synthesizing and catabolizing ATP, while lipid anabolism is inhibited, and PUFAs necessary for lipid peroxidation are also inhibited, with associated ferroptosis (Figure 2) [32]. Lee et al. [33] found that although a partial tumor suppressor role of the AMPK pathway has been established in cell death experiments due to ROS induction and/or energy depletion through glucose starvation experiments, they have also found that the AMPK pathway can be activated to protect cells from ferroptosis by reducing the amount of ROS produced by the AMPK pathway. However, their studies and multiple validations have also established that affecting AMPK inhibits ferroptosis and that the pro-tumorigenic function of AMPK is mediated, at least in part, through its ability to inhibit ferroptosis under certain circumstances. A study of TIGAR [34], a highly relevant potential regulator of colorectal cancer, has found that TIGAR promotes tumor cells because it can induce ferroptosis resistance in colorectal cancer cells through the AMPK signaling pathway, which in turn ensures the viability of tumor cells. These two findings confirm that activation of the AMPK signaling pathway maintains the resistance of tumor cells to ferroptosis, and that inhibition of this pathway is not a way to promote the occurrence of ferroptosis in cells.

Figure 2:

Signaling pathway of MAPK.

E-cadherin-NF2-Hippo-YAP/TAZ pathway

Mechanistically, the regulatory effect of the E-cadherin-NF2-Hippo-YAP pathway on ferroptosis results from cell-to-cell contacts mediated by epithelial cell calreticulin (E-cadherin) [35], a cell-to-cell interaction that can activate the intracellular Hippo signaling pathway via NF2 tumor suppressor proteins to inhibit the nuclear translocation of the tumor protein YAP and the transcriptional activity of the tumor protein YAP [36, 37]. While YAP targets several ferroptosis regulators [38], including ACSL4, transferrin receptor TfR1, etc., the occurrence of ferroptosis is therefore ultimately dependent on the activity of the Hippo pathway, and promotion of both the Hippo pathway and inhibition of YAP can inhibit ferroptosis, and vice versa triggers cell death (Figure 3). Yang’s [37] team found that renal tumor cells under different density conditions showed different sensitivities to iron ions, and by studying the cell density regulation of the Hippo-YAP/TAZ pathway, it was confirmed that TAZ in this pathway could regulate the expression of EMP1, which in turn induced the expression of NOX4. In turn, NOX4 [39], a kidney-enriched ROS-generating enzyme, is essential for ferritin deposition and can influence the onset of ferroptosis in cells. Results from another research team [40] suggest that a number of non-genetic factors may also modulate ferroptosis sensitivity in a “stiff” tumor environment known to activate YAP/TAZ and promote ferroptosis. Since higher YAP/TAZ activity promotes invasion and metastasis and is often associated with poor prognosis, triggering ferroptosis may be valuable in combination therapy for tumors that are resistant to standard therapy, especially YAP/TAZ-activated tumors.

Figure 3:

Signaling pathway of E-cadherin-NF2-Hippo-YAP/TAZ.

MBOAT1 and MBOAT2

MBOAT1 and MBOAT2 [36] are membrane-bound O-acyltransferase-containing structural domains, and MBOAT is able to stimulate 1-acylglycerophosphorylcholine O-acyltransferase activity, 1-acylglycerophosphatidylethanolamine O-acyltransferase activity, and 1-acylglycerophosphatidylserine O-acyltransferase activity. Involved in phosphatidylcholine acyl chain remodeling, phosphatidylethanolamine acyl chain remodeling and phosphatidylserine acyl chain remodeling. It is located in the endoplasmic reticulum membrane, where it is active. Liang’s [41] research team, through a genome-wide CRISPR activation screen and subsequent mechanistic studies, found that the phospholipid-modifying enzymes MBOAT1 and MBOAT2 are iron-mutagenic repressors, and that MBOAT1/2 repress iron mutations by remodeling cellular phospholipid structure. Specifically, MBOAT can convert endogenous or exogenous monounsaturated fatty acids (MUFA) to phospholipid precursor molecules such as lysophosphatidylethanolamine (lyso-PE) to synthesize MUFA-rich phospholipids. These MUFA-rich phospholipids can replace the easily oxidized PUFA (polyunsaturated fatty acids), thus reducing cell damage by ferroptosis inducers [42]. Their ferroptosis monitoring function is independent of GPX4 or FSP1. Estrogen Receptor (ER) or Androgen Receptor (AR) [43] antagonists, in combination with induced ferritin deposition, significantly inhibit the growth of ER-regulated breast cancers and AR-regulated prostate cancers. This is a novel regulatory target that offers additional potential for iron death in breast and prostate cancer.

TRIM25

TRIM25 is a 17 beta-estradiol and type I IFN-inducible E3 Ligase, encoded by the TRIM25 gene [44], it belongs to the TRIM family of proteins that can participate in protein–protein interactions and in RNA binding, and TRIM25 has been shown to be involved in a number of cellular processes such as development, innate antiviral immunity and tumor progression [45]. TRIM25 has been reported to be associated with tumor growth by increasing p53 levels through inhibition of its ubiquitination and 26S proteasomal degradation, and also by regulating p53 signaling through interaction with androgen-induced GTPase-activating protein-binding protein 2 protein [46]. In the study from Takayama et al. [47], they found that TRIM25 can also promote cell survival and growth by directly targeting Keap1 for ubiquitination and degradation, leading to Nrf2 activation, which activates antioxidant defense and ameliorates oxidative stress, suggesting that alteration of TRIM25 expression can trigger cellular peroxidation. Currently, Li et al. [48] experimentally verified that a small molecule compound, N6F11, can selectively induce ferroptosis in cancer cells without triggering ferroptosisin immune cells by activating TRIM25-mediated ubiquitination degradation of GPX4 protein (Figure 4). This study not only reveals the structural basis of the mechanism of TRIM25-mediated degradation of GPX4 protein but also offers the possibility of prompting iron death only in tumor cells while maintaining the effectiveness and safety of immune cells.

Figure 4:

Mediation of GPX4 through TRIM25.

To date, researchers have found that tumor cells are also able to undergo ferroptosis via lipid metabolism pathway, iron metabolism pathway, p53-SAT1-ALOX15, P62-Keep1-NRF2, ATG5/7-NCOA4, and FSP1-COQ10-NADPH pathway, etc. The discovery of these mechanistic pathways provides more possibilities to promote iron death in tumor cells.

Potential application of iron death in tumor therapy

Currently, the traditional treatments for tumors in the clinic are radiotherapy, chemotherapy, immunotherapy, etc. [49]. Although the wide application of radiotherapy in the clinic has assisted in the treatment of a large number of cancer cases, the wide tolerance of tumor cells is the main reason for the failure of radiotherapy, and ferroptosis has been found in radiotherapy and immunotherapy, and researchers have ventured to hypothesize that inducing ferroptosis of tumor cells may be a potential strategy for overcoming the traditional mechanisms of resistance to tumor therapy, and can make up for the shortcomings of radiotherapy treatments [50].

Existing studies [51], [52], [53] have shown that interferon gamma (IFNγ) released by CD8 T cells down-regulates the expression of two subunits of the glutamate-cystine antitransporter System Xc-, SLC3A2 and SLC7A11, and inhibits cystine uptake by tumor cells, thereby promoting lipid peroxidation and iron death. Wang’s [51] team exploited this mechanism by using programmed death ligand 8 (PD-L1) blockade and lipid peroxidation as functional markers of iron death to treat ID1 ovarian tumor-bearing mice, as well as experiments that quantified the number of infiltrating CD8 cells and the expression levels of tumor SLC7A11 and SLC3A2 in human melanoma tissues, and used both in vivo data and in vitro cultures that appeared to be hypo-cystine to show that iron death is involved in T-cell mediated immunity to tumors. The team used the data to suggest that cystine limitation may be a potential endogenous trigger for iron death in tumor cells in the tumor microenvironment (TME).

Metabolic remodeling [54] (also known as metabolic reprogramming) is a hallmark of malignant tumors, it plays a critical role in tumor persistence, and in some cases, it may affect cells to be more sensitive to iron ions. This finding exhibits a potential physiological function of ferroptosis in tumor suppression and immune monitoring, and targeting tumor ferroptosis-associated metabolism may enhance the effectiveness of cancer immunotherapy. For example, in the study of Wei et al. [55], a conjugate, AlbA-DCA, was developed, which induced a significant increase in intracellular ROS and alleviated the accumulation of lactate in TME. Meanwhile, AlbA-DCA selectively kills cancer cells and exhibits a favorable synergistic effect. Mechanistic studies have confirmed that AlbA-DCA induces apoptosis and ferroptosis.

Summarizing and looking ahead

Ferroptosis is a metabolically regulated form of cell death, caused by damage to the cell membrane due to the accumulation of lipid peroxides. In response to the characteristics of tumor cells with greatly increased oxygen demand, it is hard not to suspect that there are specific ferroptosis resistance mechanisms in tumor cells, and the current research investigation also confirms this viewpoint, and targeted destruction of these mechanisms can accelerate the occurrence of ferroptosis in tumor cells, which will provide new ideas and possibilities for the treatment of tumors. Combined with the precision targeting technology of CRISPR, and a chemodynamic therapy (CDT) for suppressing malignant tumors that has emerged in recent years [56]. We anticipate that the targeting of ferroptosis-related genes will reach a new height of precision. The application of ferroptosis in tumors has the potential to be a new therapeutic strategy, but some challenges still need to be solved, including cell specificity, therapeutic toxicity, drug development and clinical translation, etc. In addition to evaluating the cytotoxic effects resulting from oxidative stress, histological and pharmacological analyses will be crucial. Determining the optimal dosage and treatment protocols for various cell types in patients is another vital aspect that requires careful consideration. Future research endeavors are poised to tackle these challenges and pave the way for innovative opportunities in the field of cancer therapy.

Corresponding author: Yuchen Liu, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen University, Shenzhen 518035, China; and Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen University, Shenzhen 518035, China, E-mail: liuyuchenmdcg@163.com

Ying Dong and Chaojie Xu contributed equally to this manuscript.

Funding source: Shenzhen Science and Technology Program

Award Identifier / Grant number: RCJC20221008092723011

Funding source: Shenzhen Science and Technology Program

Award Identifier / Grant number: JCYJ20220818102001002

Funding source: grants from the National Key R&D Program of China

Award Identifier / Grant number: 2021YFA0911600

Acknowledgments

Ying Dong, Chaojie Xu and Jinli Guo wrote this manuscript. Yuchen Liu revised the manuscript. Thanks to the authors for their hard work on this review.

Research ethics: This review does not address ethics.
Informed consent: Informed consent was obtained from all individuals included in this study.
Author contributions: Ying Dong, Chaojie Xu and Jinli Guo wrote this manuscript. Yuchen Liu revised the manuscript.
Competing interests: Authors state no conflict of interest.
Research funding: This work was supported by grants from the National Key R&D Program of China (2021YFA0911600), Shenzhen Science and Technology Program (Grant No. RCJC20221008092723011 and JCYJ20220818102001002).
Data availability: Not applicable.

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Received: 2023-11-10

Accepted: 2023-12-07

Published Online: 2024-01-01

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/oncologie-2023-0513

Keywords for this article

ferroptosis; cancer therapy; System Xc-/GPX4 pathway; MBOAT1 and MBOAT2

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BY 4.0