Mechanism of action of cuproptosis and prospects for anti-tumor therapy

Abstract

In the study published in the World Journal of Clinical Cases by Xu et al, the expression profiles of cuproptosis-related genes in esophageal cancer and their prognostic significance were investigated. Cuproptosis, a novel form of copper-dependent cell death, has garnered significant attention in cancer research due to its mechanism closely linked to mitochondrial metabolism and protein lipoylation. This research systematically analyzed the prognostic value of cuproptosis-related genes by integrating multi-omics data from 151 esophageal cancer and normal tissue samples. The study identified pyruvate dehydrogenase A1 (PDHA1) as an independent prognostic marker for esophageal cancer. Patients with high PDHA1 expression exhibited significantly lower overall survival rates. Functional enrichment analysis further revealed that cuproptosis drives tumor progression by regulating mitochondrial tricarboxylic acid cycle activity and metabolic reprogramming of glucose metabolism. Long non-coding RNAs (LncRNAs), RNA molecules exceeding 200 nucleotides that do not encode proteins, have been extensively examined in this context. In specific tumor types, certain LncRNAs play a role in regulating cuproptosis by influencing copper ion metabolism, transport, and associated signaling pathways. These LncRNAs may interact with pivotal genes involved in cuproptosis, modulating their expression levels and participating in the regulation of this process. Current research has concentrated on the correlation between cuproptosis-linked LncRNAs and diverse cancers. A comprehensive investigation into the connections among LncRNAs, cuproptosis-related genes, pathways, and their impact on tumor drug resistance holds promise for precise cancer treatment and prognosis assessment.

Key Words: Cuproptosis; Long non-coding RNAs; Colorectal cancer

Core Tip: This study reveals that copper ion-induced precipitation modifies mitochondrial proteins, promoting cell death. Low expression of the associated gene pyruvate dehydrogenase A1 is significantly correlated with improved overall survival in esophageal cancer patients. Tumor cells, characterized by disturbances in copper metabolism, display increased susceptibility to cuproptosis, eliciting diverse outcomes in distinct tumor types. Therefore, investigating the roles of cuproptosis-related genes and long non-coding RNAs in various tumors provides new directions for precision therapies targeting the cuproptosis pathway.

TO THE EDITOR

We commend the publication of the high-quality article by Xu et al[1] in the World Journal of Clinical Cases. Through extensive data analysis, this study constructed a prognostic model linking cuproptosis-related genes to esophageal cancer, aiming to identify key genes for predicting patient outcomes. This work provides novel insights and potential therapeutic targets for advancing precision treatment strategies in esophageal cancer. The pivotal aspect of cuproptosis is the disruption of copper ion homeostasis. Excessive copper ions interact with lipoylated proteins in the mitochondrial TCA cycle, induce reactive oxygen species production, and initiate proteotoxic stress, culminating in cell death. Crucial genes such as ferredoxin 1 (FDX1). It is an iron-sulfur protein located in the mitochondrial matrix. and LncRNAs like Metastasis-Associated Lung Adenocarcinoma Transcript 1, is a LncRNAs, are instrumental in this regulation, influencing tumor cell sensitivity to cuproptosis. The development of personalized prognostic models based on cuproptosis-related factors is instrumental in identifying susceptible patients and achieving targeted therapy. However, it remains imperative to delve deeper into the mechanisms of cuproptosis, particularly its interactions with the tumor microenvironment, to uncover more potential therapeutic targets and enhance its clinical application in tumor treatment.

Copper, an essential trace element in the human body, plays a critical role in physiological processes. It serves as a cofactor for numerous enzymes, participating in various biochemical reactions through electron transfer, essential for normal cellular function. Additionally, copper ions contribute to the metabolism of iron ions and influence hemoglobin synthesis, which is vital for maintaining normal hematopoietic function[2,3].

Research indicates that cuproptosis plays a significant role in the onset and progression of tumors. Abnormal expressions of cuproptosis-related genes and imbalances in copper metabolism have been identified in various tumors, including breast, lung, liver, colorectal, pancreatic, ovarian, and gastric cancers. Tumor cells exhibit heightened sensitivity to copper, and their growth, metastasis, and angiogenesis are intricately linked to copper homeostasis. Consequently, targeting cuproptosis could be crucial in tumor treatment. A thorough understanding of the mechanisms underlying cuproptosis is essential for developing novel anti-tumor therapies and enhancing cancer prognosis[4-6].

Copper ion metabolism and homeostasis imbalance

Copper, an essential trace element, primarily enters the human body through absorption in the small intestine. The copper transporter 1 (CTR1, also known as solute carrier family 31 member 1, SLC31A1) on the surface of small intestinal epithelial cells facilitates the uptake of copper ions. These ions are then transferred across the cell by the copper chaperone antioxidant 1 and subsequently enter the bloodstream via the ATPase copper transporter α (ATP7A). In circulation, approximately 75% of the copper ions bind to ceruloplasmin in a non-exchangeable form, 25% to human serum albumin in an exchangeable form, and a minor portion to histidine. The ions are eventually transported to the liver and may be excreted into the bile through the ATPase copper transporter β, thus maintaining copper ion homeostasis within the body. Normally, cellular copper ion concentration is stringently regulated; however, disturbances such as excessive copper intake or impaired excretion can disrupt this balance, leading to the accumulation of excessive copper ions, a critical precursor to cuproptosis[3,7,8].

The difference between cuproptosis and other programmed cell deaths

Cuproptosis exhibits distinct mechanistic differences from other programmed cell death modalities, such as apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis[3,7,8].

Apoptosis, mediated by the caspase family, is activated through either the intrinsic mitochondrial pathway or extrinsic death receptor pathway. In the intrinsic pathway, cellular stress disrupts the balance of Bcl-2 family proteins, leading to pro-apoptotic protein activation, increased mitochondrial membrane permeability, cytochrome c release, and subsequent activation of caspase-9 and downstream executioner caspases (e.g., caspase-3/7), culminating in apoptosis. The extrinsic pathway is characterized by the binding of ligands to death receptors such as Fas/CD95, leading to the assembly of the death-inducing signaling complex and subsequent activation of caspase-8, a pivotal event in initiating the caspase cascade. Apoptotic cells exhibit characteristic features like cell shrinkage, chromatin condensation, DNA fragmentation, and apoptotic body formation[7].

Necrosis, an uncontrolled form of cell demise induced by severe insults such as hypoxia or physical and chemical damage, is characterized by swift cellular swelling, membrane disruption, and the elicitation of an inflammatory reaction stemming from the release of cytoplasmic contents. In contrast, cuproptosis represents a programmed cell death pathway that is selectively triggered by an overabundance of copper ions, exhibiting precise molecular orchestration that sets it apart from necrosis[7].

Autophagy, a self-degradative process, encompasses the generation of autophagosomes to sequester defective organelles/proteins, subsequently subjecting them to lysosomal breakdown to uphold cellular equilibrium. While controlled autophagy fosters cell viability during stressful conditions, immoderate autophagy can precipitate cellular demise. Its modulation involves intricate pathways like the mTOR (mechanistic Target of Rapamycin is a serine/threonine protein kinase) signaling axis. In contrast, cuproptosis does not activate autophagic degradation mechanisms but primarily interferes with mitochondrial respiration and metabolic pathways[7].

Pyroptosis, driven by inflammasome activation such as NLRP3 in response to pathogen detection or danger cues, represents a form of programmed cell death. The formation of the inflammasome triggers the activation of caspase-1, which cleaves gasdermin proteins to generate pores in the plasma membrane, causing lytic death and inflammatory cytokine release[7].

Ferroptosis, a form of cell death dependent on iron levels, is initiated by iron accumulation and subsequent lipid peroxidation via Fenton reactions. Excessive reactive oxygen species target polyunsaturated fatty acids within cell membranes, leading to oxidative cell death. In contrast, cuproptosis is copper-dependent and primarily involves the excessive binding of Cu²⁺ to lipoylated proteins within the mitochondrial TCA cycle. This interaction results in protein aggregation, disruption of iron-sulfur cluster proteins, and proteotoxic stress, ultimately culminating in caspase-independent cell death with unique morphological features[7].

Analysis of the relationship between cuproptosis and LncRNA

Regulation of Cuproptosis by LncRNA. In certain tumor studies, specific LncRNAs have been observed to influence the sensitivity of cells to cuproptosis by modulating genes or pathways associated with this cell death modality[8,9]. For instance, in liver cancer cells, some LncRNAs may affect the cuproptosis process by altering the expression or activity of crucial cuproptosis-related proteins such as FDX1. If an LncRNA suppresses FDX1 expression, it could diminish the cells' sensitivity to cuproptosis. Conversely, enhancing FDX1 function through LncRNA regulation could increase the propensity for cuproptosis.

Influence of Cuproptosis on LncRNA. The cellular stress responses and metabolic alterations induced by cuproptosis can, in turn, influence the expression of LncRNAs. As cells undergo cuproptosis, modifications in the intracellular redox state and mitochondrial function occur. These alterations may serve as signaling events that trigger transcriptional activation or inhibition of specific LncRNAs[10].

Mechanisms of LncRNA regulation in cuproptosis

LncRNAs have the capacity to modulate cuproptosis by controlling the expression of copper ion transporters, thereby impacting intracellular copper ion levels. Previous studies spropose that specific LncRNAs could target copper transporters such as CTR1 and ATP7A. Dysregulation of these transporters by LncRNAs may disrupt the balance of copper accumulation or efflux, thereby influencing the occurrence of cuproptosis. For instance, in cancerous cells, the elevation of CTR1 Levels by LncRNAs might enhance copper uptake, potentially sensitizing cells to cuproptosis. Conversely, the inhibition of CTR1 expression may reduce cellular susceptibility to cuproptosis[3].

Mitochondria play a pivotal role in cuproptosis, and LncRNAs can influence this process by regulating genes associated with mitochondrial function. Studies indicate that some LncRNAs modulate the expression of genes involved in the mitochondrial respiratory chain and the tricarboxylic acid (TCA) cycle. Alterations in the expression of these genes by LncRNAs may disrupt mitochondrial energy metabolism and redox homeostasis, thereby affecting the interaction between copper ions and mitochondrial proteins and ultimately modulating cuproptosis.

LncRNAs also regulate cuproptosis by participating in multiple signaling pathways. Pathways such as PI3K/AKT/mTOR and Wnt/β-catenin, which are intricately associated with cell proliferation and survival, exhibit interconnectedness with cuproptosis. Certain LncRNAs interact with key molecules within these pathways, influencing their activation or suppression and indirectly modulating cuproptosis. For instance, in some tumor cells, LncRNAs may suppress the PI3K/AKT/mTOR pathway, increasing cellular sensitivity to cuproptosis. Conversely, in different contexts, LncRNAs may activate the Wnt/β-catenin pathway, thereby inhibiting cuproptosis[7,8].

Different effects of cuproptosis and LncRNA on tumors

Some studies suggest that certain LncRNAs promote the survival and proliferation of tumor cells by inhibiting cuproptosis. These LncRNAs may establish intricate regulatory networks within tumor cells, engaging with other signaling pathways to collectively maintain the malignant phenotype of tumor cells. Research has found that cuproptosis-related LncRNAs in breast cancer are closely associated with the proliferation, invasion, and metastasis of tumor cells. These LncRNAs have the potential to impact the biological behavior of breast cancer cells by regulating copper ion homeostasis. For instance, certain LncRNAs might bind to the promoter regions of copper transporter genes or cuproptosis effector protein genes, repressing their transcription, reducing intracellular copper ion accumulation, or decreasing the occurrence of cuproptosis, thereby providing a survival advantage to tumor cells and promoting tumor growth and metastasis. Additionally, cuproptosis-related LncRNAs may also be linked to endocrine therapy and targeted therapy resistance in breast cancer[11].

In the field of lung cancer research, the dysregulated expression of cuproptosis-associated genes is intricately linked to the initiation and advancement of tumors. Specific LncRNAs play a role in modulating the proliferation, apoptosis, and metastasis of lung cancer cells by governing copper ion metabolism and cuproptosis signaling pathways. These LncRNAs can impact intracellular copper ion levels by regulating copper ion uptake and transportation, thereby influencing the sensitivity of lung cancer cells to cuproptosis. Elevated expression of certain LncRNAs may bolster the resistance of lung cancer cells to cuproptosis, fostering tumor progression, whereas reduced expression levels may heighten cell susceptibility to cuproptosis, impeding tumor development[12].

In liver cancer, cuproptosis-related LncRNAs also play a significant role. They contribute to tumorigenesis by influencing energy metabolism and responses to oxidative stress in liver cancer cells. Certain LncRNAs have the ability to modulate the cellular distribution and metabolism of copper ions, impacting the viability and proliferation of liver cancer cells. Moreover, cuproptosis-related LncRNAs may interact with the immune microenvironment of liver cancer, affecting tumor immune evasion and the efficacy of immunotherapy. Some LncRNAs have been found to enhance cuproptosis, exerting tumor-suppressive effects. These LncRNAs may upregulate the expression of cuproptosis-related genes, promote copper ion uptake, or enhance the activity of cuproptosis signaling pathways, ultimately inducing cell death in tumors[7].

Analysis of copper death-related LncRNAs in tumor prognosis prediction

In the risk stratification and survival prediction for multiple tumors, prognostic models based on cuproptosis-related LncRNAs have exhibited strong predictive capabilities[13]. By analyzing the expression profiles of these LncRNAs across numerous tumor samples, patients can be categorized into distinct risk groups[10]. For instance, in lung cancer, patients with high expression levels of specific cuproptosis-related LncRNAs generally exhibit poorer overall survival rates, whereas those in the low-expression group demonstrate more favorable survival outcomes[8].

Some copper death-related LncRNAs exhibit differential expression between tumor tissues and normal tissues, rendering them as promising biomarkers for tumor diagnostics. Through the identification of copper death-related LncRNAs, predictive models can be constructed to assess patient prognosis. For example, in gastric cancer, specific copper death-related LncRNAs exhibit markedly elevated expression levels in tumor tissues as compared to normal gastric mucosa tissues. The assessment of the expression levels of these LncRNAs in serum or tissues can facilitate early gastric cancer detection. In cancer research, a model based on SNHG16, LENG8-AS1, LINC0225, and RPARP-AS1 has demonstrated efficacy in distinguishing high-risk from low-risk patients and forecasting patient survival outcomes[10,11]. In lung adenocarcinoma research, a prognostic model composed of 16 copper death-related LncRNAs has shown the ability to accurately predict overall survival and progression-free survival among patients. These models help doctors to more precisely assess patient statuses and provide valuable insights for clinical interventions[12].

The relationship between mitochondrial metabolism-related genes and cuproptosis

Multiple genes are pivotal in linking cuproptosis with mitochondrial metabolism. For instance, FDX1 serves as a significant regulatory factor in the cuproptosis process, managing the protein lipoylation process. Under the influence of copper ions, FDX1 may facilitate the reduction of copper ions from divalent to monovalent states, thereby modulating the activity of downstream proteins. Furthermore, genes such as lipoic acid synthetase (LIAS) and lipoyltransferase 1 participate in the lipoylation pathway. Together with dihydrolipoamide S-acetyltransferase and others, they constitute a gene network integral to cuproptosis. The aberrant expression of these genes disrupts normal mitochondrial metabolism and the cuproptosis process, subsequently impacting cell survival and proliferation. For example, in certain tumors, the aberrant expression of FDX1 correlates strongly with the sensitivity of tumor cells to cuproptosis[8,9].

Anti-tumor treatment with novel copper ion carriers

Copper ionophores have been instrumental in elucidating the mechanism of cuproptosis. Agents such as elesclomol and disulfiram have been demonstrated to induce cell death by facilitating the transport of copper ions into cells and mitochondria, thereby initiating cuproptosis. However, most current clinical studies indicate that these drugs do not yield significant clinical benefits in unselected populations. Consequently, researchers are actively pursuing the development of novel copper ionophores. These emerging compounds are expected to possess superior physicochemical properties, which could enhance the selective targeting of tumor cells and augment anti-tumor efficacy[3,7].

Combination therapy strategy and personalized therapy strategy

Considering the intimate connection between cuproptosis and mitochondrial metabolism, and the heightened mitochondrial metabolic activity observed in certain tumor cells, employing a combination of copper ionophores and small-molecule drugs targeting mitochondrial metabolism-related targets may represent an effective treatment strategy[14]. For instance, the concomitant use of drugs targeting Epidermal Growth Factor Receptor or B-cell lymphoma-2 and other relevant targets could potentially yield a synergistic effect in tumor therapy[3,7].

Differences in cuproptosis-related gene expression, mitochondrial metabolic levels, and other factors are observed across various tumor types and individual tumor cells. Consequently, implementing a personalized treatment strategy is essential. This strategy involves selecting the optimal treatment plan tailored to the specific characteristics of the patient's tumor, including gene expression profiles and copper ion metabolism status. For instance, by assessing the expression levels of cuproptosis-related genes, such as FDX1 and LIAS, in tumor tissues, clinicians can identify patient subsets potentially more responsive to treatments inducing cuproptosis, thus facilitating targeted therapeutic interventions[8].

Modulating the immune microenvironment to enhance the efficacy of immunotherapy

Hypoxia within the tumor microenvironment can suppress the expression of cuproptosis-related proteins, such as FDX1, diminishing the susceptibility of tumor cells to cuproptosis and consequently impacting the effectiveness of cuproptosis-induced therapies[14-16]. Therefore, addressing tumor hypoxia represents a crucial strategy to augment the therapeutic efficacy of cuproptosis. Strategies such as enhancing oxygen delivery or employing hyperbaric oxygen therapy may increase the oxygen availability in tumor tissues, potentially amplifying the activity of cuproptosis inducers and improving the efficiency of tumor cell eradication[3,7].

Copper ions can modulate the expression of immune-related molecules within the tumor microenvironment, such as impacting PD-L1(Programmed Death-Ligand 1) expression and thus influencing tumor immune evasion. Therefore, integrating cuproptosis-induced therapy with immunotherapy could yield synergistic effects. On one hand, cuproptosis-induced cell death may release more tumor-associated antigens, thereby activating the host immune response. On the other hand, adjusting the function of immune cells in the immune microenvironment, such as enhancing the maturation and activation of dendritic cells and promoting the proliferation and function of CD8⁺ T cells, may enhance the body’s immune surveillance and tumor eradication capacity. Future studies should investigate optimizing the tumor immune microenvironment via cuproptosis-induced treatments to improve anti-tumor immunotherapy outcomes[8,15,16].

CONCLUSION

This study demonstrates that cuproptosis constitutes an independent mode of cell death, intricately linked to mitochondrial metabolism and specific gene regulation. It highlights the critical roles of key genes such as FDX1 in the cuproptosis process and the efficacy of copper ionophores in inducing this form of cell death. Additionally, the study elucidates the metabolic pathways of copper ions within cells and their relationship to the biological behaviors of tumor cells. These findings suggest a novel potential target for cancer therapy. Inducing cuproptosis in tumor cells could selectively eliminate malignant cells while minimizing harm to normal tissues. This approach may enhance the effectiveness of integrated treatment strategies, deepen the understanding of tumor cell biology, and support the development of more precise methods for tumor diagnosis and prognosis assessment.