Cuproptosis in prostate cancer: Molecular mechanisms, prognostic biomarkers and therapeutic frontiers of cuproptosis‑related genes (Review)

Introduction

Prostate cancer (PCa) is among the most prevalent malignancies in males globally and has emerged as a notable public health concern (1). The pathophysiology of PCa is intricate and early-stage symptoms often go undetected; however, as the condition progresses, it may markedly affect the prognosis of patients and treatment efficacy (2,3). Androgen pathway inhibitors and chemotherapeutic medicines act as first-line therapeutic options for PCa, while prostate-specific antigen testing, multi-parametric magnetic resonance imaging and positron emission tomography-computed tomography imaging function as first-line diagnostic techniques, considerably enhancing the survival rates and prognosis of patients. Despite advancements in medical technology and the growing complexity of diagnostic and therapeutic approaches for PCa, the treatment and prognosis remain poor due to delayed diagnosis, postoperative recurrence, complications, complexities in treatment and resistance (4-6). For example, the effectiveness of non-selective immune checkpoint inhibitor therapy in patients remains ambiguous and its application in the early stages of treatment-resistant clones may promote the emergence of highly cross-resistant clones, thereby diminishing the clinical efficacy of subsequent androgen pathway inhibitor therapy (7). Thus, further investigations are required, to determine the specific pathophysiology of PCa and identify novel treatment targets that may improve patient prognoses.

In ~1980, researchers demonstrated that copper may be associated with programmed cell death (8). In 2022, Tsvetkov et al (9) highlighted a novel mechanism of copper-induced cell death; namely, cuproptosis (9). The results of this previous study provided novel insights into the role of copper in tumor growth. Cuproptosis is an emerging form of cell death in PCa, with evidence suggesting that it suppresses tumor progression. Inducing cuproptosis or modulating cuproptosis-related genes (CRGs) may exhibit potential as novel anti-cancer therapies. Thus, further investigations are required to determine the specific processes associated with cuproptosis and the potential role it may play in PCa.

Copper metabolism and mechanisms underlying cuproptosis

Copper is vital for numerous biological functions (10). In mammals, copper is derived from food and is absorbed by intestinal epithelial cells in the duodenum and small intestine (11), a process that is carried out by copper transporter 1 (CTR1). Notably, this protein is located at the tip of intestinal epithelial cells and is mediated by the metal-reducing enzyme prostate six transmembrane epithelial antigen (STEAP) with duodenal cytochrome b activity. This activity prompts the reduction of Cu2+ to Cu+ (12,13), which is transferred to the bloodstream via the copper ion transport ATPase alpha peptide (ATP7A) (14). Upon entering the bloodstream, copper associates with soluble copper carrier proteins, referred to as copper chaperones (such as SLC31A1), which are transported by CTR1 and absorbed via the portal circulation system to reach the liver (15-19). Within hepatocytes, copper is released into the bloodstream via the ATPase copper ion transport, ATPase beta peptide (ATP7B), which subsequently binds to copper cyanoproteins and albumin, facilitating transport to other tissues in the body (20). Upon reaching target tissues, copper catalyzes reactions in various physiological processes (21-24). When copper levels in the body surpass the expected threshold, hepatocytes transport copper through ATP7B to bile and this travels through the bile ducts into the intestines, before being expelled in feces (25).

However, excessive accumulation of intracellular copper ions may be harmful to cells (26). Results of a previous study (27) indicated that excessively high copper levels promote the generation of reactive oxygen species (ROS), resulting in oxidative stress and DNA damage that may lead to cell death. Alterations in the valence state of copper ions result in harm to bio-organic molecules, including proteins, nucleic acids and lipids. These alterations may disrupt the production of iron-sulfur (Fe-S) clusters; thus, impacting enzyme activity (28). Excess copper ions associate with the lipoylated constituents of the tricarboxylic acid cycle (TCA) within mitochondria. Ferredoxin 1 (FDX1), a member of the ferredoxin protein family, co-regulates the proteolipoylation of proteins, such as dihydrolipoic acid S-acetyltransferase (DLAT) and lipoic acid synthetase (LIAS). FDX1 reduces Cu2+ to Cu+, which exhibits higher levels of toxicity. This ion subsequently binds to lipoylated proteins, causing DLAT aggregation, resulting in proteotoxic stress and cellular apoptosis. Moreover, Cu+ may destabilize the architecture of Fe-S cluster proteins and impede the synthesis of Fe-S proteins, which are integral to mitochondrial stability. The depletion of Fe-S cluster proteins markedly compromises cellular metabolic functions and energy maintenance, leading to an escalation of oxidative free radicals and the production of ROS, thereby increasing cytotoxicity and culminating in cell death (Fig. 1). In addition, FDX1 and LIAS may be affected by cuproptosis, resulting in reduced expression (9,29,30). Thus, the homeostatic management of copper is crucial to avert cytotoxicity and sustain overall health. Notably, the processes and attributes of cuproptosis may exhibit potential in the treatment of specific disorders.

Figure 1 Processes of copper metabolism and cuproptosis. Cu2+ are reduced to Cu+ by STEAP/DCYTB in the gut epithelium and transported into cells via CTR1. Inside target cells, Cu+ interferes with Fe-S clusters, generates ROS and leads to mitochondrial dysfunction. Excess Cu+ induces protein aggregation via lipoylated proteins, mediated by FDX1 and LIAS, ultimately causing cuproptosis. STEAP, prostate six transmembrane epithelial antigen; DCYTB, duodenal cytochrome b; CTR1, copper transporter 1; TCA, tricarboxylic acid cycle; Fe-S, iron-sulfur; ROS, reactive oxygen species; FDX1, ferredoxin 1; DLAT, dihydrolipoamide S-acetyltransferase; LIAS, lipoic acid synthetase.

Role of copper in tumor metabolism

The identification of cuproptosis has offered novel insights into the initiation and advancement of tumor pathologies. Copper participates in the biological mechanisms of tumor proliferation and migration during the initial stages, activating metastasis-associated enzymes and signaling pathways to facilitate the spread of cancer (26). Notably, it binds to and activates critical molecules within various tumor signaling pathways (31,32), thereby influencing cancers directly or indirectly, and is intricately associated with the regulation of anti-tumor immunity (33). Moreover, copper directly influences or indirectly modifies the activity of key components, such as the Notch system; thus, affecting tumor angiogenesis, metabolism and inflammatory response (34). Copper also plays a key role in cancer cell proliferation (35) and results of a previous study (36) revealed that metallothionein, which is associated with copper storage, was markedly diminished in tumor tissues. Collectively, these results suggest that the capacity of cancer cells for regulating copper levels may be compromised. Moreover, copper facilitates angiogenesis, which is intricately associated with the advancement of malignant tumors (37,38). Results of previous studies (39-41) demonstrate that copper may activate numerous angiogenic factors and stabilize nuclear hypoxia-inducible factor-1, thereby augmenting the expression of pro-angiogenic factors. In addition, copper facilitated angiogenesis in numerous in vitro and in vivo models, whereas copper chelators inhibited tumor angiogenesis (42). Results of a further previous study (43) revealed that increased copper concentrations in tumor cells facilitated tumor angiogenesis, resulting in tumor advancement and spread. Consequently, increased copper concentrations may facilitate tumor development and progression. Excess copper levels may lead to cytotoxicity and trigger cuproptosis, which suppress tumor progression. Notably, excess copper-induced cuproptosis may exert inhibitory effects in numerous types of cancer (44). Copper exerts a dual influence on tumors and their metabolism, facilitating tumor cell proliferation and differentiation, while simultaneously suppressing proliferation and triggering apoptosis. This phenomenon is intricately associated with its biochemical characteristics and the complex tumor microenvironment (45).

Current status of cuproptosis research in PCa

Cuproptosis and the progression of PCa

Elevated copper concentrations in PCa cell tissues are a hallmark of patients with PCa (46), as demonstrated using in vitro cell line studies (47-49) and a xenograft mouse model (49,50). Notably, patients with PCa exhibit higher than expected serum copper levels (51-53) and elevated serum copper levels may be associated with a poor prognosis in patients with PCa (54). The RNA interference-mediated knockdown of CTR1 decreased copper ion absorption in PCa cells, resulting in the substantial inhibition of tumor growth (50). Collectively, these findings highlighted the role that increased copper ion concentrations may play in sustaining the biological processes of PCa cells, while diminished copper ion levels may fail to support the physiological functions of tumor cells.

Results of a previous study (31) reveal that the expression levels of CRGs in several types of tumor were markedly associated with patient prognosis, indicating that cuproptosis may play a key role in tumor biology and therapeutic response. Results of previous studies (51,55-60) indicate that individuals with malignant tumors, including PCa, exhibit markedly altered levels of Cu in both serum and tumor tissues. Moreover, CRGs play a role in PCa through predicting prognosis, modulating the tumor microenvironment and affecting therapeutic response (54). A range of CRGs may affect the progression of PCa, with CRGs and corresponding functions associated with cuproptosis detailed in Table I. At present, research is focused on the potential of cuproptosis in preventing tumor growth. Consequently, the manipulation of cuproptosis or CRGs has emerged as a viable anti-cancer therapy.

Table I Targets and roles of PCa-related CRGs in the cuproptosis process.

Table I

Targets and roles of PCa-related CRGs in the cuproptosis process.

First author/s, year	Designation (of an object)	Target of action	Role in cuproptosis	(Refs.)
Yang, 2022; Yang, 2024	FDX1	Sites of lipoylation modification, Cu2+	Engaged in the lipoylation modification of proteins (DLAT, among others); Reduction of Cu2+ to the more hazardous Cu+ resulting in cuproptosis	(61,62)
Yang, 2023	DLAT	Lipoylated protein, Cu2+	Cuproptosis triggered by lipoylation oligomerization	(63)
Yang, 2022	LIAS	Lipoylated protein	Regulated by FDX1, involved in lipid acylation pathway	(61)
Li, 2024	DLD		Engaged in TCA, wherein lipid acylation interacts with copper ions to trigger cuproptosis	(64)
Xiao, 2023	GCSH			(65)
Li, 2024	PDHA1			(64)
Li, 2024	DBT		Key enzyme in TCA, binds to copper ions to induce cuproptosis	(64)
Zhang, 2023	CDKN2A	Cellular cycle and p53 signaling pathway	Regulates the cell cycle and copper metabolism while inhibiting cuproptosis	(66)
Li, 2024	GLS	Metabolic route of glutamine	Oxidative stress in the TCA cycle mitigates tumors and prevents the occurrence of cuproptosis	(64)
Lin, 2024	NUDT21	Genes associated with DHA biosynthesis and copper ion transport-related proteins	Demethylation of these genes/proteins induces shortening of the 3′UTR, thereby suppressing DHA biosynthesis and conferring insensitivity to cuproptosis	(67)

[i] PCa, prostate cancer; CRGs, cuproptosis-related genes; TCA, tricarboxylic acid cycle; FDX1, ferredoxin 1; DLAT, dihydrolipoamide S-acetyltransferase; LIAS, lipoic acid synthase; DLD, dihydrolipoamide dehydrogenase; GCSH, glycine cleavage system protein H; PDHA1, pyruvate dehydrogenase E1 subunit alpha 1; DBT, dihydrolipoamide branched-chain transacylase E2; CDKN2A, cyclin-dependent kinase inhibitor 2A; GLS, glutaminase; NUDT21, nudix hydrolase 21; DHA, docosahexaenoic acid; 3′UTR, 3′ untranslated region.

Mechanisms underlying cuproptosis in PCa

Mitochondrial dysfunction is pivotal for cuproptosis, resulting in oxidative damage to the mitochondrial membrane and compromised enzyme performance in the TCA cycle (29). By contrast, excessive copper accumulation in cellular mitochondria initiates cuproptosis (68), producing substantial amounts of ROS. During PCa progression, ROS levels are increased in PCa cells (69), resulting in DNA mutations, oncogene activation and tumor suppressor gene inactivation. This cascade facilitates malignant cell transformation and the activation of stress-responsive survival pathways, thereby exacerbating the aberrant proliferation of PCa cells (70). In addition, the process of cuproptosis generates ROS, further advancing PCa progression (71). Notably, a requisite level of ROS is essential for tumor cell growth and DNA mutation; however, severe oxidative stress may deplete the capabilities of the antioxidant system, resulting in apoptosis (72). In cuproptosis, ROS are continuously generated, leading to toxic concentrations in PCa cells and notable effects on tumor growth. Results of previous studies (73-75) indicate that the excessive creation and accumulation of ROS are employed to impede PCa progression. Moreover, soy isoflavones, such as genistein and soy glycosides, may elevate copper concentrations in PCa cells through mobilizing endogenous copper and disrupting the expression of copper transporter protein genes, CTR1 and ATP7A, in cancer cells. This process subsequently induced high levels of ROS production, ultimately resulting in apoptosis in PCa cells (76). Moreover, curcumin analogs (77) and felicidin (78) exhibit analogous mechanisms of action to impede PCa cell proliferation. Results of a previous study (79) reveal that alterations in the ATP7B gene inhibits the regulation of copper ion distribution in vivo, resulting in increased copper levels in PCa cells. Similarly, ATP7B protein levels were markedly enhanced in docetaxel-resistant PCa cell lines, resulting in diminished intracellular copper levels. Notably, these levels may be promoted through silencing ATP7B expression or using a combination of disulfiram and copper to enhance intracellular copper concentrations (80). This modified intra- and extracellular copper distribution results in a substantial inhibitory effect on PCa growth, which may be associated with the excessive production of ROS due to copper ion carriers entering PCa cells, as well as antioxidant deficiencies present in these cells (79). Results of a previous study (81) highlight a reciprocal interaction between cuproptosis and copper-induced oxidative stress. The accumulation of ROS may facilitate the progression of PCa and exert an inhibitory effect on it. Cuproptosis may induce excessive ROS production to promote tumor cell death; however, investigations surrounding this dual mechanism are limited (Fig. 2). The specific impact of cuproptosis on PCa requires further validation through relevant experiments to elucidate the mechanism underlying cuproptosis in the context of PCa development.

Figure 2 Dual mechanisms underlying copper and cuproptosis in PCa. Mitochondrial dysfunction is central to cuproptosis, leading to oxidative damage and inhibition of the TCA cycle. Excess copper accumulation in mitochondria triggers cuproptosis and sustained ROS production. Moderate ROS levels promote DNA mutations and oncogenic signaling, driving tumor progression. In contrast, excessive ROS overwhelm antioxidant defenses and induce tumor cell death. The specific involvement in PCa requires further validation. PCa, prostate cancer; TCA, tricarboxylic acid cycle; ROS, reactive oxygen species.

Copper participates in tumor metabolism and promotes tumor progression. Notably, copper is associated with the progression and spread of PCa (82,83) and it also facilitates tumor angiogenesis (37,38). Angiogenesis markedly contributes to the progression and metastasis of PCa (84), primarily driven by angiogenic factors, including vascular endothelial growth factor, fibroblast growth factor, hypoxia-inducible factor (HIF) and interleukin (85). Results of a previous study (79) reveal that a reduction in copper levels diminishes HIF activity and obstructed tumor angiogenesis. Moreover, restrictions in angiogenesis may limit PCa progression (86). Copper chelators may also diminish intracellular copper ion concentrations and lower copper bioavailability, thereby reducing copper-induced angiogenesis (42). Therefore, lowering copper concentrations to impede tumor angiogenesis may mitigate tumor advancement.

Complexities in lipid metabolism may contribute to carcinogenesis and disease progression. Results of a previous study (87) reveal that disturbances in lipid metabolism are associated with disease advancement and the development of castration-resistant prostate cancer (CRPC). In addition, cholesteryl esters (CE) are excessively accumulated in high-grade PCa and metastatic sites (88). The Wnt/β-catenin signaling pathway plays an important role in the metastasis of PCa and the depletion of CE markedly obstructs Wnt3a secretion through reducing unsaturated fatty acid levels, which inhibit the activation of the Wnt/β-catenin signaling pathway and restrict the acylation of Wnt3a, thereby inhibiting the metastasis of PCa (89). Copper ions also activate the Wnt/β-catenin signaling pathway, resulting in augmented cancer stem cell characteristics and increased resistance to numerous therapies (90). Elevated serum copper levels may be associated with increased serum total cholesterol and HDL cholesterol levels, as well as a heightened risk of dyslipidemia characterized by high serum total cholesterol and LDL cholesterol (91). Results of previous studies (92,93) reveal that zebrafish and grass carp exhibit elevated copper concentrations in their livers when subjected to excess copper, resulting in increased lipid accumulation and levels of triglycerides. These findings indicate that alterations in copper levels, particularly in excess, may influence the progression of PCa by affecting lipid metabolism and signaling system activity; however, further molecular or animal studies are required to validate these mechanisms.

In conclusion, the mechanisms underlying cuproptosis in PCa primarily encompass oxidative stress, intracellular copper distribution, angiogenesis and lipid metabolism dysregulation. Further investigations into these mechanisms may facilitate a deeper comprehension of cuproptosis in PCa and aid in identifying potential therapeutic targets.

Integrated therapeutic approaches for PCa predicated on cuproptosis, including carriers of copper ions

Elesclomol (ES) is a copper ion transporter that facilitates the entry of copper ions into cells, often targeting mitochondria. The entry of copper into cells leads to the accumulation of ROS, consequently impeding tumor growth. In cancer therapy, ES may leverage its capacity to produce cuproptosis to eliminate malignant cells. Disulfiram (DSF) functions as a copper ion transporter through binding to copper ions and facilitating entry into the cell. Notably, DSF has previously been investigated for the treatment of specific types of cancer, particularly those with elevated levels of lipoylated proteins (94). The two aforementioned copper ion carriers have been extensively researched for their ability to carry Cu2+ into cells or mitochondria to facilitate copper-dependent cell death (Fig. 3). Copper exerts a multifaceted impact on PCa growth and proliferation; however, results of in vitro studies (61,62) consistently demonstrate that ES diminishes PCa cell viability via a reduction in FDX1 expression levels. Moreover, ES promotes keratin formation in tumor cells, inhibits autophagy in PCa via the DLAT/mammalian target of rapamycin pathway and enhances sensitivity to docetaxel and paclitaxel chemotherapy (95). In addition, DSF compounds combined with copper have demonstrated efficacy in breast cancer treatment through downregulating the expression of the phosphatase and tensin homolog (PTEN) associated with human chromosome 10 deletion and activating protein kinase B (AKT) signaling. This indicates a potential for combination therapy utilizing phosphatidylinositol 3-kinase (PI3K)/AKT inhibitors (96). Results of further previous studies (97,98) reveal that PCa may involve the same PTEN and PI3K/AKT signaling pathways for targeted therapy, highlighting that these pathways may inhibit PCa progression. However, previous investigations focused on the role of PTEN and PI3K/AKT signaling pathways in PCa progression remain limited.

Figure 3 Mechanism of copper ion carriers. Elesclomol and disulfiram enhance intracellular Cu+ accumulation in tumor cells. In the presence of elevated lipoylated proteins or ALDH expression (such as PCa), Cu+ induces toxic stress within mitochondria, triggering cuproptosis and resulting in tumor cell death. ALDH, acetaldehyde dehydrogenase; PCa, prostate cancer.

Moreover, ES may exhibit potential in the treatment of PCa. Results of a previous study (99) revealed that DSF may inhibit the proliferation of PCa cell lines and this mechanism may be mediated by other pharmacological agents or specific sensitizers, such as copper (100). Thus, copper may be used to suppress the growth of PCa cells (49,101), ultimately improving the survival rate of patients (80).

Collectively, these results revealed that although copper ion carrier-induced cell death is a key form of cell death, few studies have confirmed the efficacy in PCa using in vitro investigations. Results of previous research demonstrated that several substances may elevate intracellular copper ion concentrations, including the aforementioned copper ion carriers, copper ion compounds and several copper chelators that inhibit the increase in copper ion levels. Triethylenetetramine dihydrochloride (102), 8-hydroxyquinoline (103), penicillamine (104), methanobactin (105), Bathocuproine disulphonate (106) and choline tetrathiomolybdate (107) are key compounds that regulate intracellular copper ion concentrations, thereby facilitating or obstructing copper ion-associated biological functions. The aforementioned drugs are theoretically capable of stimulating cell proliferation; however, no previous investigations have been undertaken regarding cuproptosis in PCa. Preliminary experiments should be performed to substantiate this hypothesis and to aid in the development of novel cuproptosis-associated therapies.

Chelators of copper ions

A reduction in glutathione (GSH), a natural chelator of intracellular copper ions, results in an elevation of intracellular copper concentration, ultimately culminating in cell death (9). In healthy prostate cells, GSH neutralizes ROS produced by increased copper ion levels from copper ion carriers; thus, providing an antioxidant effect and reducing sensitivity to ROS. Conversely, PCa cells possess diminished levels of GSH and are deficient in antioxidants, rendering them susceptible to ROS generated by copper ion carriers. Subsequently, this may result in PCa cell mortality (79). In addition, elevated copper concentrations facilitate tumor angiogenesis and disrupt lipid metabolism. Steroid-based compounds impede PCa progression through the inhibition of CTR, thereby decreasing copper absorption by PCa cells and mitigating the proliferative effects of copper. These results indicate that the aforementioned compounds may represent innovative anticancer agents targeting anti-copper therapy (35). Results of a further study (108) reveal that the pro-drug, gamma-glutamyl transferase-activated prochelator releasing dithiocarbamate (GGTDTC), is activated by gamma-glutamyl transferase (GGT) in PCa cells. The release of dithiocarbamate (DTC), which chelates with copper ions to form a Cu-DTC complex, is highly toxic and promotes PCa cell death by triggering oxidative stress to generate large amounts of ROS. Ultimately, this interferes with protein ubiquitination. In PCa cells, GGT is often overexpressed and the concentration of copper ions is high. In addition, GGT exhibits a decreased antioxidant capacity, leading to metabolic disorders. This compound is more selective to cancer cells and therefore less toxic to non-tumor cells. In addition, GGT exhibits improved selectivity (108). Thus, the use of copper chelators, in addition to elevated copper ion concentrations that mediate cuproptosis and impede tumor advancement, may diminish intracellular copper levels and initiate cuproptosis. These compounds may be used to leverage the highly toxic characteristics of copper-chelator complexes, which may further inhibit tumor progression to some degree. However, the specific mechanisms remain to be fully elucidated.

Copper nanoparticles

Nanotechnology facilitates the targeted delivery of copper ions to tumor sites via modifying responsive groups that coordinate with copper compounds. This process enhances the concentration of copper ions within tumor cells, leading to the toxic oligomerization of lipoylated proteins and the degradation of Fe-S cluster proteins. This ultimately induces cuproptosis in tumor cells and produces a therapeutic effect against cancer (109). Researchers presented a novel nanoparticle, DCM@GDY-CuMOF@DOX, capable of releasing Cu+ in the presence of GSH, ultimately facilitating the onset of cuproptosis (110). Concurrently, doxorubicin (DOX) generates high levels of hydrogen peroxide (H2O2), which, when catalyzed by Cu+, is transformed into cytotoxic ROS via a Fenton-like reaction. Notably, this process induces cancer cell death. ROS produced via this method may trigger apoptosis, resulting in oxidative DNA damage and mitochondrial impairment. By contrast to the administration of DOX alone, nanoparticles enveloped within the PCa cell membranes (DU145 cell membrane; DCM) exhibit isotypic targeting capabilities, allowing them to specifically identify and target identical PCa cells. This process may diminish the likelihood of non-specific targeting during blood circulation. The non-specific adsorption and elimination in the bloodstream extend circulation time within the body, thereby minimizing toxicity to healthy tissues and enhancing the precision of targeting PCa cells for treatment. Haemolysis experiments, histopathological assessments and serum biochemical analyses demonstrated that nanoparticles did not induce notable damage to healthy cells and tissues; however, they did exhibit targeting capabilities and biocompatibility. Thus, these may exhibit potential in clinical practice (110). Results of a previous study (111) demonstrate that cuprous oxide nanoparticles (CONPs) selectively inhibited the proliferation of CRPC cells. Toxicological investigations revealed that CONPs elevate copper demand and uptake capacity and induce cell cycle arrest and apoptosis in cancer cells. In addition, CONPs suppressed stem cell properties and the Wnt signaling pathway and exhibited minimal effects on healthy prostate epithelial cells. Moreover, Cu(DDC)2 nanoparticles facilitate the transport of Cu2+ into cells, elevate intracellular copper levels and mediate the apoptosis of paclitaxel-resistant PCa cells (112). These nanoparticles facilitated tumor site-specific accumulation and induce cuproptosis through loading copper ions and employing a responsive release mechanism, offering a novel, targeted and biocompatible therapeutic alternative for PCa treatment.

Moreover, liposomal copper (LpCu) effectively transports copper ions into PCa cells via encapsulating copper salts within liposomes. PCa cells treated with LpCu exhibit metabolic toxicity comparable with that of free copper salts, indicated by increased intracellular copper levels and increased levels of ROS, apoptosis and necrosis (113). Specific steroid-based compounds form complexes with copper ions, diminishing the concentration of free copper ions within the cell. Thus, the influx of copper ions into PCa cells via CTR1 is reduced, effectively impeding copper absorption by PCa cells and disrupting their biosynthesis to inhibit PCa cell proliferation (35).

Adjuvant therapy and targeted prediction of cuproptosis in PCa

Surgery remains the primary treatment option for localized PCa and androgen deprivation therapy is effective for patients with biochemically recurrent and metastatic hormone-sensitive PCa. However, resistance and progression to CRPC may still occur, along with suboptimal therapeutic outcomes following chemotherapy and immunotherapy (54). At present, research is focused on the role of cuproptosis in malignancies, to determine the effects on cell growth and the specific underlying mechanisms.

Cuproptosis affects treatment resistance and contributes to the management of PCa. Notably, enzalutamide augments the susceptibility of CRPC cells to copper ion carriers and improves treatment efficacy through facilitating copper-dependent cell death. This combination therapy efficiently suppresses the proliferation of CRPC cells and reverses the resistance of enzalutamide-resistant cells both in vitro and in vivo (43). By contrast, enzalutamide-resistant PCa cells demonstrate high levels of resistance to cuproptosis and the alteration of NUDT21 activity or the addition of PDHA improve the effectiveness of the copper ionophore, potentially leading to treatment resistance in PCa (67). Results of a further previous study revealed that a combination of disulfiram and copper led to a notable reduction in the expression of ATP7B and the elevation of intracellular copper levels in PCa cell lines, rendering resistant cells sensitive to the growth-inhibitory and apoptotic effects of docetaxel (80). Results of both in vivo and in vitro studies demonstrate that a combination of DSF and copper markedly reduces cell proliferation and the induction of apoptosis, indicative of the increased antitumor efficacy of docetaxel (80). Moreover, DSF and copper directly interact with ATP7B, leading to the downregulation of its downstream proteins, including copper metabolism MURR1 Domain containing 1, α-clusterin and S-phase kinase associated protein 2. Simultaneously, DSF and copper promote upregulation of cyclin-dependent kinase inhibitor 1 thus inhibiting tumor growth (80). Results of a previous study (95) reveal that a combination of ES and CuCl2 (ES-Cu) effectively induces copper-mediated cytotoxicity in PCa cells, inhibits autophagy via DLAT upregulation and subsequently promotes cell retention in the G2/M phase, thereby augmenting the chemotherapeutic efficacy of docetaxel. In vivo experiments further demonstrate that the combination of ES-Cu and docetaxel markedly suppresses tumor growth in a PCa transplantation model using nude mice, where tumor proliferation was markedly inhibited (95). Collectively, these data indicated that copper-induced cell death may impact the sensitivity of PCa to pharmacological agents.

Complanatoside A (CA) is a flavonoid derived from the Traditional Chinese Medicine, Semen Astragali Complanati. Results of a previous study (114) reveal that CA downregulates the expression of the copper efflux-associated protein, ATOX1, promotes the accumulation of intracellular copper ions, inhibits mitochondrial activity and induces copper-mediated cell death. Notably, this agent markedly suppresses the proliferation, invasion and growth of PCa cells both in vivo and ex vivo, with no notable damage to major organs in experimental animal models (114). Nuclear factor-activated T cell 5 (NFAT5) is a transcription factor that activates T cells and plays a key role in cellular stress response, immunological response and cell proliferation. Results of previous study revealed that NFAT5 acts as a target gene of microRNA (miR)-206 through bioinformatics analysis and database predictions. In addition, results of a previous study (115) reveal that the long-chain non-coding RNA (lncRNA), AP000842.3, acts as a target gene of miR-206, functioning as a competitive endogenous RNA (ceRNA) that modulates the expression levels of NFAT5. Thus, this lncRNA affects the sensitivity of PCa cells to copper death inducers. In cellular experiments, NFAT5 knockdown markedly increases the sensitivity of PCa cells to copper-induced cytotoxicity and this was highlighted by elevated intracellular copper ion concentrations and reduced ROS levels (115). Therefore, the interaction of lncRNA AP000842.3 with miR-206 may play a key role in regulating NFAT5 expression. Notably, this regulatory mechanism may be partly dependent on miR-206, providing a novel potential target for PCa diagnosis and treatment (115).

Resveratrol, a polyphenol compound mainly located in red grapes and pomegranates, is an antioxidant that inhibits PCa cells through interacting with copper ions. This process contributes to the redox of copper ions and the generation of ROS, leading to an increase in intracellular oxidative stress and interference with intracellular signaling pathways, such as MAPK, PI3K/Akt and NF-κB pathways. Moreover, results of a this study (116) reveal that resveratrol inhibits cell cycle progression, thus inhibiting PCa cell proliferation. This compound also activates key intracellular apoptotic signaling pathways, such as the mitochondrial pathway and death receptor pathway, to promote the apoptosis of PCa cells. By contrast, copper ion chelation reverses the anticancer effects of resveratrol, further confirming the key role of copper ions in the action of resveratrol. In addition, the observed elevation of copper ions may facilitate their absorption and storage, promoting the harmful effects of resveratrol through the upregulation of the copper transporter protein, CTR (116). Collectively, results of these investigations indicated that copper and copper-induced cytotoxicity may serve as viable therapeutic approaches for the treatment of PCa.

Despite the limited number of studies on cuproptosis in PCa, previous studies revealed that CRGs may act as novel therapeutic targets, playing a key role in the progression of PCa (Table II). Moreover, cuproptosis may be associated with key predictors of PCa, exhibiting potential as a novel indicator of the prognosis of patients with PCa and their responsiveness to treatment (Table III).

Table II Correlation between CRGs and PCa.

Table II

Correlation between CRGs and PCa.

First author/s, year	CRGs	Sources for screening	Association with PCa	(Refs.)
Yang, 2022; Yang, 2024; Wang, 2023	FDX1	Genome-wide screening utilizing CRISPR/Cas9 technology	Elevated expression correlates with unfavorable prognosis; Inverse connection with immune cell infiltration, cellular autophagy and drug sensitivity	(61,62,117)
Yang, 2023; Wang, 2023	DLAT		Elevated expression correlates with favorable prognosis and positively connected with immune cell infiltration	(63,117)
Yang, 2024; Wang, 2023	LIAS		Elevated expression correlates with a favorable outcome	(62,117)
Li, 2024; Wang, 2023; Cheng, 2023	PDHA1		Elevated expression correlates with diminished bad prognosis, treatment resistance and DFS	(64,117,118)
Wang, 2023	CDKN2A DLD		Elevated expression correlated with unfavorable prognosis and decreased DFS	(117)
Li, 2024; Wang, 2023	GLS		Elevated expression correlates with unfavorable prognosis	(64,117)
Xiao, 2023	GCSH	Analysis of expression levels using the StarBase and GEPIA databases		(65)
Yang, 2024; Li, 2024	DBT	Analysis of differential expression in TCGA and GEO datasets	Elevated expression correlates with a favorable outcome	(62,64)

[i] CRGs, cuproptosis-related genes; PCa, prostate cancer; FDX1, ferredoxin 1; DLAT, dihydrolipoamide S-acetyltransferase; LIAS, lipoic acid synthase; PDHA1, pyruvate dehydrogenase E1 subunit alpha 1; CDKN2A, cyclin-dependent kinase inhibitor 2A; DLD, dihydrolipoamide dehydrogenase; GLS, glutaminase; GCSH, glycine cleavage system protein H; DBT, dihydrolipoamide branched-chain transacylase E2; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9; DFS, disease-free survival; GEPIA, Gene Expression Profiling Interactive Analysis; TCGA, The Cancer Genome Atlas; GEO, Gene Expression Omnibus.

Table III Summary of PCa prediction models based on cuproptosis.

Table III

Summary of PCa prediction models based on cuproptosis.

First author/s, year	Forecasting model	Construction methods	Forecasting metrics	Prominent application domains in PCa	(Refs.)
Yang, 2024; Li, 2024; Wang, 2023	CRGs	Sequential LASSO Cox regression	FDX1, DLAT, DLD, PDHA1, CDKN2A, DBT, GLS and others	Assessment of relapse risk, treatment efficacy and DFS	(62,64,117)
Jin, 2022	CRGs evaluations	Univariate Cox regression	DLAT, FDX1, DLD, LIAS, GLS, PDHA1, CDKN2A and others	Recommendations for individualized immunotherapy approaches	(119)
Wang, 2024	Gleason scores and CRGs	LASSO Cox and multifactorial Cox regression	Five particular genes (STX3, CABLES2, E2F5, RALA and POLE3)	Personalized therapy and administration	(120)
Yao, 2023	Cuproptosis-related immunization risk score		Three immune-related CRGs (PRLR, DES and LECT2)	Evaluation of OS and DFS	(121)
Zhang, 2023	CRGs and PCa expression correlate		Five particular genes (B4GALNT4, FAM83D, COL1A, CHRM3 and MYBPC1)	Prediction of responsiveness to chemotherapy and immunotherapy	(122)
Ma, 2024	Necrosis and CRGs		CDI	Assessment of survival and recurrence risk	(123)
Cheng, 2023	CRLs related with cuproptosis		Six CRLs	DFS prognosis, evaluation of the immune microenvironment	(124)
Ma, 2023			Twelve CRLs	Evaluation of OS and DFS	(125)
Jiang, 2022			Six CRLs	DFS evaluation	(126)
Zhong, 2025					(127)
Ren, 2023				Assessment of relapse risk	(128)
Yu, 2024					(129)
Lu, 2024			Three CRLs	Prognostic assessment for progression-free survival	(130)

[i] CRGs, cuproptosis-related genes; PCa, prostate cancer; FDX1, ferredoxin 1; DLAT, dihydrolipoamide S-acetyltransferase; DLD, dihydrolipoamide dehydrogenase; PDHA1, pyruvate dehydrogenase E1 subunit alpha 1; CDKN2A, cyclin-dependent kinase inhibitor 2A; DBT, dihydrolipoamide branched-chain transacylase E2; GLS, glutaminase; LIAS, lipoic acid synthase; STX3, syntaxin 3; CABLES2, Cdk5 and Abl enzyme substrate 2; E2F5, E2F transcription factor 5; RALA, RAS-like proto-oncogene A; POLE3, DNA polymerase epsilon 3; PRLR, prolactin receptor; DES, desmin; LECT2, lectin-like transcript 2; B4GALNT4, beta-1,4-galactosyltransferase 4; FAM83D, family with sequence similarity 83 member D; COL1A, collagen type I alpha; CHRM3, cholinergic receptor muscarinic 3; MYBPC1, myosin binding protein C 1; DFS, disease-free survival; OS, overall survival; CDI, cell death index; CRLs, cuproptosis-related long non-coding RNAs.

Irrespective of the trajectory of predictive modeling, research is focused on the development of novel molecular instruments for prognostic evaluation and clinical decision-making in PCa. Cuproptosis-based prognostic models exhibit efficacy in predicting outcomes of patients with PCa; however, the recurrence prediction mediated by CDI surpasses that of the cuproptosis-based prognostic models (123). CRLs obtained from bioinformatics analysis not only aid in the establishment of a prognostic prediction model for patients with PCa, but also the results of cellular experiments reveal that the knockdown of CRLs, particularly AC106820.5, may inhibit the proliferation, migration and invasive capabilities of PCa cells (127). Collectively, these data illustrate that bioinformatics analyses may be used to identify potential therapeutic targets in the treatment of PCa. Notably, the aforementioned models may also be used to predict responsiveness to immunotherapy, leading to the development of personalized treatment options that improve patient outcomes and quality of life.

Discussion

The redox activity of copper represents a dual purpose in cellular viability; for example, it acts as a crucial cofactor for enzymes that facilitate vital physiological processes in cellular metabolism and may induce oxidative stress and cell death when present in excess (131,132). The initial discovery of cuproptosis elucidated the association between copper-induced cell death and mitochondrial metabolism, thus furthering investigations in copper biology and offering novel insights for future investigations into cell death pathways. In PCa, increased copper concentrations and a disruption of copper transporters result in the accumulation of copper ions within tumor cells, facilitating the initiation of cuproptosis. The activation of cuproptosis facilitates the elimination of surplus copper ions, mitigates cellular damage resulting from copper metabolism disorders and suppresses the proliferation, invasion and metastasis of PCa cells, thereby inhibiting tumor progression induced by copper metabolism disorders. However, further investigations are required to determine the specific underlying mechanisms.

In recent years, cuproptosis has become a novel focus within PCa research, demonstrating potential in various tumors to markedly impact the proliferation, invasion and metastasis of tumor cells. Despite novel insights into the role of cuproptosis in PCa, this field of study exhibits certain limitations. Cuproptosis may inhibit the progression of PCa; however, PCa requires elevated copper levels for its physiological functions. In addition, FDX1 expression in PCa cells remains low to prevent the initiation of cuproptosis. Androgens may enhance the transcriptional levels of CTR1, ATP7B and STEAP in PCa cells via androgen receptor activation, thereby increasing copper uptake and facilitating PCa progression (49). Moreover, the hypothesis regarding increased copper demand in PCa and the approaches to alleviate levels of toxicity remain ambiguous and the specific molecular mechanisms underlying cuproptosis have yet to be fully elucidated. Thus, further investigations should focus on the specific signaling pathways and regulatory mechanisms underlying this phenomenon. Notably, these processes may include the accumulation of copper ions in PCa cells, the functions of pivotal proteins and the activation of signaling pathways associated with the onset of cuproptosis. To date, previous research has focused on CRGs and CRLs and the use of bioinformatics analyses, predictive model development and in vitro experimentation. The aforementioned studies have primarily utilized public databases for analysis, which may result in limitations in the validity of studies, through large-scale clinical samples and a lack of investigation into clinical applications. Thus, further investigations should focus on the use of genetic analysis of clinical samples to validate prior findings and inform subsequent studies. Notably, the AlphaFold (https://deepmind.google/science/alphafold/) suite of tools constitutes a robust, integrated platform for structural prediction. It is used to accurately predict the structures of proteins interacting with various biomolecules (133). Thus, the development of novel prediction models using AlphaFold 3 tools may further the understanding of PCa at the molecular level and aid in the identification of additional therapeutic targets. Further investigations into drug sensitivity may lead to the development of novel therapeutic targets, while analyses of immune cells inside the tumor microenvironment may clarify the role of cuproptosis in modulating their activity and the potential impact on tumor proliferation and metastasis. Moreover, a multidisciplinary research approach is required to elucidate the specific role of cuproptosis in PCa, thereby establishing a foundation for the advancement of novel therapies aimed at enhancing the prognosis and quality of life of patients.

In conclusion, the present review article demonstrated that cuproptosis may exhibit potential in the treatment of PCa. Notably, copper-based nanomedicines, as well as traditional copper ion carriers and chelators, may elicit more potent anti-tumor effects. Additional investigations into the transformation of conventional pharmaceuticals into nanoparticles, alongside additional clinical trials, may aid in the development of a novel therapeutic approach. However, these trials should be preceded by a comprehensive understanding of the mechanisms underlying copper metabolism and cuproptosis, aiming to determine distinct interactions between copper and the tumor microenvironment, as well as immune responses, which are essential for drug design and efficacy prediction. Notably, the identification of cuproptosis has prompted extensive investigations into novel treatment options for PCa and this newly recognized mechanism of regulatory cell death may contribute to theoretical advancements and practical implementations in the field.

Availability of data and materials

Not applicable.

Authors' contributions

ZL was responsible for writing the original draft, reviewing and editing, project administration, supervision and conceptualization. YC was responsible for writing the original draft, reviewing and editing, supervision and visualization. KZ was responsible for writing the original draft, supervision and conceptualization. ZC was responsible for writing the original draft and resources. YY was responsible for funding acquisition, supervision, project administration, writing, reviewing and editing. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant nos. 81503589, 81973866 and 82474520), the Natural Science Foundation of Sichuan Province (grant no. 2022NSFSC0684) and the Sichuan Provincial Administration of Traditional Chinese Medicine Science and Technology Research Special Fund Project (grant no. 2021ZD016).

References