Roles of zinc in cancers: From altered metabolism to therapeutic applications

Zinc (Zn) is a crucial trace element involved in various cellular processes, including oxidative stress, apoptosis and immune response, contributing to cellular homeostasis. Dysregulation of Zn homeostasis occurs in certain cancers. This review discusses the role of Zn in cancer and its associated components, such as Zn‐related proteins, their potential as biomarkers and the use of Zn‐based strategies for tumor treatment. ZIP and ZnT proteins regulate Zn metabolism under normal conditions, but their expression is aberrant in cancer. These Zn proteins can serve as prognostic or diagnostic biomarkers, aiding in early cancer detection and disease monitoring. Moreover, targeting Zn and its pathways offers potential therapeutic approaches for cancer treatment. Modulating Zn biodistribution within cells using metal‐binding agents allows for the control of downstream signaling pathways. Direct utilization of zinc as a therapeutic agent, including Zn supplementation or Zn oxide nanoparticle administration, holds promise for improving the prognosis of cancer patients.

1][12] Consequently, significant therapeutic strategies have been developed to exploit or address trace elements.This article presents a curated selection of pivotal studies exploring the cellular mechanisms linking dysregulated Zn homeostasis to cancer, while acknowledging conflicting findings in this field.Additionally, it examines key therapeutic approaches that focus on Zn or utilize it as a central element in cancer treatment.

| ZINC METABOLISM IN NORMAL CONDITIONS
Zinc is an essential and abundant trace element in humans, ranking second only to iron.Zinc exists in our organism as a divalent cation, capable of forming tetrahedral complexes.Within cells, Zn exists in two forms: protein-bound Zn and mobilizable Zn, which is bound by unidentified non-protein ligands. 13Approximately 300 enzymes rely on Zn for their activity, and about 2000 transcription factors depend on Zn for maintaining their structural integrity.These transcription factors possess Zn finger domains that coordinate Zn cations, stabilizing their structure and folding. 14Consequently, Zn plays a critical role in numerous cellular processes, including oxidative stress, apoptosis and the immune response. 15Furthermore, Zn is implicated in various pathophysiological conditions, such as growth retardation, hypogonadism, neurosensory and cognitive disorders, cardiovascular disease, diabetes mellitus and cancer. 2,16Of the 2 g of Zn present in the human body, 99.9% is found within cells, while the remainder is in the blood plasma. 17Unlike Cu and Fe, 18,19 Zn absorption does not necessitate oxidation or reduction processes. 20

| Zinc homeostasis
Zinc homeostasis is primarily maintained by two families of Zn transporters that function in opposing directions.The first family, known as ZnTs (or solute carrier 30/SLC30) consists of 10 members, while the second family, called ZIPs (or Zrt-and Irt-like proteins or solute carrier 39/SLC39) comprises 14 members.ZnTs facilitate the export of Zn from the cytosol to the extracellular medium or intracellular compartments, whereas ZIPs increase the cytosolic Zn concentration (Table 1).The ZIP family is further divided into four subfamilies, with nine human members belonging to the LIV-1 subfamily. 21Intracellular Zn sensing is mediated by the Zn-dependent metal regulatory transcription factor 1 (MTF-1). 2 MTF-1 possesses six cysteine2-histidine2 (Cys2-His2) Zn fingers that serve as DNA-binding domains. 22In response to Zn, MTF-1 regulates the expression of various genes, including those encoding ZnT1, ZnT2 and metallothioneins (MTs). 2,23tallothioneins, with high Zn affinity, act as major intracellular Znbinding proteins. 24These small, cysteine-rich proteins govern the storage and release of intracellular Zn. 25 Less than 1% of total Zn is found in the serum, with $80% bound to serum albumin and 20% to α2-macroglobulin 26 (Figure 1).

| Zinc signaling
Zinc plays a vital role in cell signaling, acting as both an extracellular neurotransmitter and an intracellular second messenger. 27Zn stimulates serine/threonine protein kinases involved in cell proliferation, differentiation and apoptosis.Among the targets of Zn signaling are the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) within the mitogen-activated protein kinase (MAPK) pathway. 2 Zn also promotes T-cell proliferation through the MAPK pathway by inhibiting the dephosphorylation of MAPK/ERK kinase (MEK) and ERK. 28Furthermore, Zn activates the signal transducer 29 and activator of transcription proteins (STAT) pathway, leading to the expression of genes associated with differentiation, survival, cell proliferation and apoptosis. 30STAT3 has been shown to increase the expression of ZIP6, promoting cell migration. 31In T-lymphocyte cells, Zn treatment activates protein kinase C, which binds to the membrane and cytoskeleton. 32Chelation of Zn inhibits these mechanisms. 33Zn is present in synaptic vesicles and participates in the activation of postsynaptic cells by being released through exocytosis and binding to ligand ion channels. 34Zn is also essential for cell division, specifically in the process of mitotic entry during the G2/M phase of the cell cycle. 35ZIP6 and ZIP10 are two Zn transporters involved in transporting Zn into cells at specific time points during the cell cycle, and their blockade prevents mitosis, emphasizing the necessity of Zn for this process.These findings suggest that targeting ZIP6 and ZIP10 may hold potential for developing therapies aimed at modulating cell division. 36ereby, Zn is an essential element in metabolism, comparable to iron and copper, and is involved in various pathological conditions.
The control of zinc homeostasis primarily relies on two families of proteins: ZnT proteins, responsible for exporting zinc from the cytosol, and ZIP proteins, which increase the level of zinc within the cytosol.
Zn also functions as a neurotransmitter and a second messenger in signaling pathways, contributing to cell division, proliferation, differentiation, survival and apoptosis.Dysregulation of zinc homeostasis and its consequences are known to contribute to a range of pathologies, including cancers, which will be further explored in the subsequent section.

| ALTERED Zn METABOLISM IN CANCER, AND Zn PROTEINS AS CANCER BIOMARKERS
The role of Zn in cancer varies depending on the type of cancer.In some cancers, high Zn levels have been associated with a reduction in telomere attrition, which is a significant cause of chromosome instability. 37Additionally, elevated Zn levels have been correlated with a decrease in the frequency of micronuclei, 38 which are chromosome fragments used as biomarkers for chromosome instability. 39erefore, Zn appears to play a protective role in maintaining DNA integrity and may help prevent cancer progression.However, the activity of Zn transporters, which are crucial for cell division, is increased in certain cancers and has been linked to poorer prognosis. 36The regulation of Zn-related proteins also differs depending on the type and stage of cancer (Table 2).

| Pancreatic cancer
Messenger RNA analysis of ZIP and ZnT proteins in human pancreatic adenocarcinoma reveals downregulation of all ZIP proteins except for ZIP4, which is upregulated. 40ZIP4 overexpression increases cell proliferation by activating the CREB pathway and promoting the silencing of miR-373 target genes, including PHLPP2, an inhibitor of pancreatic cancer cell proliferation 41 leading to cell proliferation and tumor progression. 42Another pathway involving ZIP4 and miR-373 leads to the inhibition of LATS2, a tumor suppressor gene, resulting in the upregulation of YAP1 and promoting pancreatic cancer metastasis. 43ZIP4 also decreases the expression of tight junction proteins ZO-1 and claudin-1, 44  cancer compared to normal tissues. 40Zn supplementation leads to upregulation of ZnT1 and induction of cytotoxicity in pancreatic cancer 45 cells through protein ubiquitination, an important mechanism for apoptosis-independent cell death. 46[49] Additionally, a significant decrease in Zn level is observed in precancerous pancreatic tissues due to decreased ZIP3 expression. 9

| Prostate cancer
The human prostate contains the highest level of Zn in the body, 50 where it plays a role in blocking citrate oxidation and promoting the production of prostatic fluid. 51Studies on the effect of Zn in prostate cancer show contradictory results.While some studies suggest that Zn supplementation may increase the risk of advanced prostate cancer, 52 the majority of research indicates that decreased Zn levels are associated with poor prognosis.Prostate cancer cells lose their ability to accumulate Zn, possibly due to the production of oxidized citrate, which inhibits Zn accumulation. 53 has the capacity to induce cell cycle arrest and apoptosis in prostate cancer cells, contributing to the inhibition of malignant cell growth. 54,55 terms of Zn transporters, ZIP1 expression is notable in normal prostate cells but is downregulated in prostate cancer. 50,56,57ZIP4 expression is also decreased in prostate carcinoma.ZIP1 and ZIP4 may function as tumor suppressors in the prostate.9][60] Monitoring Zn status, along with prostate-specific antigen, can provide a more specific approach to diagnosing prostate cancer. 61ZIP9, in association with testosterone, induces apoptosis in a similar manner to breast cancer cells. 62,63More details are given in breast cancer section.
Metallothioneins are major Zn-binding proteins and serve as tumor markers in prostate cancer.The level of MT in the serum of prostate cancer-diagnosed patients is consistently increased. 64MTs are also used as markers for head and neck tumors, melanoma and to differentiate between malignant and benign tumors in various cancers, including prostate cancer. 65

| Breast cancer
Tamoxifen is a commonly used treatment for estrogen receptor (ER)-positive breast cancers. 66However, over time, resistance to tamoxifen (TamR) can develop, leading to cancer cells that can proliferate and metastasize in the presence of the drug. 67Studies have shown that TamR cells have higher levels of Zn compared to tamoxifen-sensitive cells, and the activity of ZIP6 and ZIP7, [68][69][70][71] which are Zn transporters, is increased in TamR cells.Zinc has been found to inhibit protein-tyrosine phosphatase 1B (PTP1B), a phosphatase enzyme that regulates various signaling pathways, including those involving epidermal growth factor receptor (EGFR), insulin receptor and proto-oncogene tyrosine-protein kinase (Src). 72e inhibition of PTP1B through Zn has a significant effect on these signaling pathways, preventing their inactivation by blocking dephosphorylation.This, in turn, affects cell growth by inducing gene expression. 69The increase in intracellular Zn levels is associated with the upregulation of ZIP7 expression.When ZIP7 is silenced using small interfering RNA (siRNA) in TamR cells, signaling pathways involving EGFR and Src are inactivated and cell migration is significantly reduced. 68I G U R E 1 General overview of Zn metabolism.which activate pathways involved in cancer progression. 9Phosphorylated ZIP7 may serve as a reliable biomarker for breast cancers.
ZIP6, also known as LIV-1, 73 is associated with ER-positive breast cancer 74 and metastatic breast cancer. 69It is found to be increased in ER-positive breast cancers. 75However, in primary breast tumors, ZIP6 is downregulated.This downregulation of ZIP6 leads to resistance to hypoxia and results in epithelial-mesenchymal transition (EMT), 76 which is a process associated with cancer progression and metastasis.Therefore, the role of ZIP6 in ER-positive breast cancer varies depending on the stage of the disease.ZIP6 serves as a reliable biomarker in breast cancers.
ZIP10 is also associated with breast cancer invasion and metastasis. 76Transcriptome analysis has shown that ZIP10 expression is higher in metastatic breast cancer cell lines compared to nonmetastatic ones. 77ZIP10 may form a complex with ZIP6 to regulate and promote EMT, 78 although further studies are needed to fully understand the mechanism of this interaction.
In breast tumors, there is a higher accumulation of Zn compared to normal cells, which can have cytotoxic effects.To counteract this, ZnT2 is overexpressed and acts as a protector by sequestering Zn into intracellular vesicles.Inhibition of ZnT2 can release the accumulated Zn from vesicles, leading to cytotoxicity in malignant breast cancer cells. 79ain metastasis from breast cancer is a significant issue.cancer has lower Zn levels.Zn levels increase with HER2 expression, and triple-positive breast cancer has higher Zn levels compared to other molecular subtypes, except for triple-negative breast cancer.
Malignant breast tissue generally exhibits higher Zn concentrations compared to the surrounding stromal area and healthy tissue. 82Zn also contributes to the binding between progesterone receptor (PR) and its receptor (PRr). 83Changes in PR-PRr signaling pathways play a role in human breast cancer progression, 84 and Zn is implicated in the cerebral cavernous malformation signaling complex pathway, which involves PR and PR and is associated with a high risk of breast cancer. 85The role of ZIP proteins in these cancer subtypes requires further investigation.
In breast and prostate cancer cells lacking nuclear androgen receptor, ZIP9 acts as a membrane androgen receptor.The interaction between ZIP9 and testosterone leads to an increase in the amount of free Zn within cells, resulting in apoptosis.However, nuclear androgen receptor agonists and other steroids do not have this effect on Zn levels. 62,63

| Lung cancer
The role of Zn in lung cancer remains not fully understood, as there are variable expression levels of ZIPs and ZnTs in lung cancer cell lines and tumors. 86ZnTs are generally downregulated, while ZIPs are upregulated in lung cancer. 87In lung tumor tissue, several genes are overexpressed, and Zn may have a preventive effect against lung cancer.
Zinc deficiency has been shown to induce DNA damage and increase the expression of apurinic endonuclease (APE), 88 which plays a crucial role in base-excision repair.Low intracellular Zn concentrations can also prevent the DNA binding activity of p53, which is a Znbinding tumor suppressor protein. 89These effects suggest that Zn deficiency may contribute to DNA damage and impair the function of tumor suppressor proteins in lung cancer.
In non-small cell lung cancer (NSCLC), ZIP4 may be overexpressed.ZIP4, through the transcription factor snail, promotes the activity of N-cadherin, leading to NSCLC metastasis. 90This upregulation of ZIP4 is associated with increased invasion properties and poor survival in patients. 91ZIP4 can serve as a biomarker for metastasis in NSCLC and may help guide personalized treatments with greater accuracy. 92erall, the role of Zn and the involvement of ZIP proteins in lung cancer require further investigation to better understand their contributions to lung cancer development, progression and metastasis.

| Hepatocarcinoma
Zinc finger proteins (ZNF) play a role in DNA transcription and replication.One of them, ZN191 has the potential to promote hepatocellular carcinoma (HCC) proliferation. 93In HCC, the role of ZnT and ZIP proteins is not yet fully understood.ZIP14, which is highly expressed at the plasma membrane of normal hepatocytes, is decreased or absent in the early stages of HCC, and this low expression level persists in the late stages of the cancer. 94The quantification of ZIP14 in liver tissues may have the potential to indicate the occurrence of HCC.
ZIP2 and ZIP9 are also decreased in HCC.ZIP9, unlike ZIP2, plays a role in macrophage polarity.M1 macrophages promote the production of reactive oxygen species (ROS) and nitric oxide (NO), while M2 macrophages are known to encourage HCC. 95,96ZIP9, through the IL4/STAT6 pathway, promotes M2 macrophage polarization and conversely, through the IκBα/β-p65 pathway, ZIP9 inhibits M1 macrophage polarization. 97 the other hand, there is a study reporting that ZIP4, ZIP14 and ZnT9 are upregulated in HCC tissue compared to adjacent nontumor liver tissue. 98However, this finding contradicts the previous study describing the low expression of ZIP14 in HCC tissue.The authors of the study reporting the upregulation of ZIP14 mention that their results need further validation.
Overall, the role and expression patterns of ZnT and ZIP proteins in HCC are complex and require additional research to fully understand their implications in HCC development, progression and potential therapeutic targeting.

| Other cancers
In glioblastoma tissue, the expression of zinc transporters is regulated differently depending on the grade.High-grade glioblastomas (grade III and IV) show upregulation of ZIP3, ZIP4, ZIP8, ZIP14, ZnT5 and ZnT7, while low-grade glioblastomas (grade I and II) exhibit upregulation of ZIP11, ZnT3, ZnT9 and ZnT10. 99,100ZIP4 is associated with poor prognosis and the expression of genes involved in cell growth and angiogenesis in glioma, suggesting it may serve as a biomarker for gliomas. 100,101 esophageal squamous cell carcinoma (ESCC), ZIP6 promotes proliferation, invasion and metastasis by activating the PI3K/AKT and MAPK/ERK pathways through an increase in intracellular zinc levels. 102,103Regulating or inhibiting zinc homeostasis could be a potential strategy to treat the aggressiveness of ESCC.
ZIP10 is upregulated in digestive cancers, which includes stomach and colon cancer. 9However, the consequences and mechanisms underlying this increase require further investigation.Overall, zinc levels are decreased in the tissue of stomach and colon carcinoma. 104 ovarian cancer, ZIP4 is upregulated, and knockout of ZIP4 significantly reduces tumorigenesis, while overexpression increases tumor development. 105ZIP4 has also been identified as a cancer stem cell (CSC) marker in epithelial ovarian cancer. 106Cancer stem cells are responsible for sustaining the growth and spread of tumors. 107 ZIP10 is highly expressed in the late stages (grade III and IV) of renal cell carcinoma, suggesting it can be used as a biomarker to confirm the aggressiveness of renal cancer. 108ZIP11 is also associated with renal cell carcinoma, but further studies are needed to understand its exact role. 109P7 promotes cell proliferation, migration and invasion in cervical cancer.Knockdown of ZIP7 leads to the expression of cell adhesion proteins and downregulation of anti-apoptotic proteins, indicating ZIP7 as a potential biomarker and therapeutic target for cervical cancer. 110sopharyngeal carcinoma shows increased expression of ZIP4, and silencing ZIP4 restores the normal epithelial phenotype and enhances the radio sensitivity of cancer cells.Targeting ZIP4 alongside radiotherapy may be a promising treatment approach for nasopharyngeal carcinoma. 111P11 is linked to bladder cancer risk, with certain variants associated with increased or reduced risk.The mechanisms and expression patterns of ZIP11 in bladder cancer require further investigation.
Bladder cancer tissue exhibits higher expression of ZnT1 compared to normal tissue, and miR-411, which regulates ZnT1, is downregulated in bladder cancer. 109Targeting ZnT1 using miR-411 or other specific compounds could be an interesting approach for bladder cancer treatment. 112P4 overexpression is also observed in oral squamous cell carcinoma (OSCC) compared to normal tissues.Deprivation of ZIP4 leads to decreased cellular growth in OSCC. 113 summary, zinc transporter proteins play varied roles in different types of cancer, and their dysregulation can contribute to cancer progression, invasion and metastasis.Understanding the specific mechanisms and functions of these zinc transporters can aid in the development of targeted therapies and identification of potential biomarkers for cancer diagnosis and prognosis.

| Targeting Zn with metal-binding compounds
The role of metals in cancer has been well recognized. 18,19,114Currently, metal-binding compounds are being investigated as potential anticancer agents. 115pending on their effects, metal-binding compounds can be classified as "metal chelators" or "metal ionophores."Metal chelators reduce the availability of a metal by forming stable complexes with it, while metal ionophores reside in the membrane bilayer and facilitate the transport of metal ions across the membrane, leading to equilibrium in the concentration of free metal ions.Ionophores act as transmembrane metal ion transporters 116 because the binding between an ionophore and a molecule is reversible, unlike the almost irreversible binding of a metal with a chelator. 117ioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is a Zn 2+ chelator that exhibits anticancer properties in prostate cancer.In prostate cancer cells deficient in ZIP1, a zinc transporter, Zn is required for the tumor suppressor effect.Clioquinol serves as a Zn delivery agent that enables Zn internalization in these cells, acting as an ionophore.The Zn-Clioquinol complex compensates for the lack of ZIP1 by increasing intracellular Zn levels. 118Clioquinol has been shown to inhibit tumor growth in animal models. 119A phase I clinical trial conducted in 2012 explored clioquinol as a treatment for various hematological malignancies, including leukemia, lymphoma and myeloma.The trial indicated minimal proteasome inhibition. 120,121thiocarbamates are metal-chelating compounds used in the treatment of melanoma and hepatic cancer.Disulfiram (DSF), a dithiocarbamate, shows enhanced therapeutic effects when combined with Zn supplementation. 122The activity of the DSF-Zn complex could be attributed to proteasome inhibition, 115 which plays a crucial role in the degradation of unfolded or ubiquitinated proteins. 123Proteasome activity is often increased in various cancers, 124 indicating that cancer cells rely more on the ubiquitinproteasome pathway than normal cells.Inhibition of the proteasome can prevent the elimination of proapoptotic factors. 125DSF, in combination with copper, is currently under investigation for the treatment of multiple myeloma. 126N,N,N-Tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN) is a Zn chelator with membrane permeability.127,128 It has been shown to induce apoptosis in several cancer cell types.129 TPEN triggers apoptosis in pancreatic cancer cells through oxidative stress and inhibition of autophagy.130 The apoptotic effect of TPEN is associated with the activation of caspase 3 and 8. Furthermore, the antiproliferative effect of TPEN in pancreatic adenocarcinoma cells is both time-and dosedependent.131 Despite the promising results, caution must be exercised regarding the use of chelators.Chelation of Zn may lead to unintended side effects. Ferroptsis, a cell death mechanism with significant potential as a cancer therapy, 132 has been shown to be suppressed by Zn chelation, thereby hindering a potential avenue for cancer treatment.133 Additionally, Zn plays a role in autophagy, a process that regulates protein quality and quantity.The role of autophagy in cancer can be either tumor-suppressive or tumor-promoting, depending on the specific type of cancer.134 The aforementioned study indicates that inhibiting autophagy through Zn chelation induces cell death in pancreatic cancer cells. 130However, it has also been reported that autophagy collaborates with apoptosis to contribute to tumorigenesis in certain cancers, including pancreatic cancer.135 Consequently, chelating Zn to inhibit autophagy may not be an appropriate therapeutic approach for such cancers. Theefore, the chelation of Zn as a therapeutic treatment should be considered on a case-by-case basis, taking into account the specific characteristics of the cancer being treated.

| Targeting Zn metabolism proteins
The dysregulation of specific Zn transporter proteins can have contrasting effects on carcinogenesis and tumor progression, depending on the type of cancer.
In pancreatic adenocarcinomas, Zn supplementation has been shown to increase cytotoxicity and upregulate ZnT1. 45ZIP4 is upregulated in pancreatic cancer, and the use of RNA interference against ZIP4 has been found to inhibit cell proliferation, migration and invasion in ZIP4-overexpressing pancreatic carcinoma cells. 136s previously discussed, ZIP4 plays a role in the miR-373 pathway, involving interactions with CREB and YAP1, and inhibition of the targeted tumor suppressor genes, PHLPP2 and LATS2.To counteract these interactions, a novel tumor suppressor called cirANAPC7 has been identified.The cirANAPC7, a circular RNA (circRNA), acts as a sponge RNA, inhibiting miR-373 and thereby allowing the action of PHLPP2 and LATS2. 41,137e oncogenic roles of ZIP4 have also been described in NSCLC, where ZIP4 promotes tumor growth and cellular invasion.Notably, ZIP4 has been found to induce resistance to cisplatin, a conventional chemotherapy drug, in NSCLC. 138Silencing ZIP4 in NSCLC has shown partial restoration of sensitivity to cisplatin, suggesting a potential therapeutic strategy. 91P1 expression is decreased in prostate cancer.However, the transfection of ZIP1 into prostatic cancer cells has been shown to restore Zn uptake and inhibit cell growth. 54,139Interestingly, the effects of ZIP4 silencing in prostate cancer cells differ from those observed in pancreatic and lung cancer.In prostate cancer, the silencing of ZIP4 has been found to increase cell proliferation, while ZIP4 overexpression inhibits invasiveness and proliferation. 140In estrogen receptor-positive breast cancer, the activation of ZIP7 is phosphorylation-dependent. Therefore, targeting this activation pathway could be a promising therapeutic approach.It has been observed that protein casein kinase 2 (CK2) induces the activation of ZIP7. 9,58This suggests that inhibitors of CK2 may prevent the phosphorylation of ZIP7, potentially serving as anticancer agents.

| Other strategies
Supplementation with Zn has shown promise as a valuable strategy in certain cancer treatments.In pancreatic cancer cells, the addition of Zn (0.01-0.5 mM) has been found to increase cytotoxicity in human adenocarcinoma cell lines, while normal human β-cells remained unaffected by Zn supplementation. 45Similarly, treating human prostate cancer cells with Zn supplementation resulted in decreased expression of intercellular adhesion molecule 1, leading to reduced tumor cell adhesion and invasiveness. 141 patients undergoing chemotherapy for colorectal cancer, oral supplementation of 70 mg of Zn daily for 16 weeks prevented fatigue and enhanced quality of life. 142Oral mucositis is a common complication of cancer chemotherapy, 143 and Zn supplementation has been shown to reduce both the frequency and severity of oral mucositis. 144,145 nanoparticles have emerged as a promising therapeutic strategy in cancer treatment.Zinc oxide nanoparticles (ZnO NPs) are considered safe substances approved by the Food and Drug Administration. 146ZnO NPs possess low toxicity, cost-effectiveness and good biocompatibility, making them attractive for various applications, including antibacterial, antidiabetic and anticancer treatments. 147,1480][151][152] These nanoparticles have been found to induce cell death, particularly apoptosis, in cancer cell lines while having no T A B L E 3 Zinc-associated treatment strategies.Ovarian cancer ZnO NPs Supplementation Induced oxidative and proteotoxic stresses [154]  adverse effects on normal fibroblasts. 152In liver cancer, ZnO NPs increased p53 expression, 153 while in ovarian cancer, ZnO NPs induced oxidative and proteotoxic stresses, leading to apoptosis. 154ble 3 summarizes the various treatment strategies associated with Zn in cancer management.

| CONCLUSIONS
Zinc is an essential chemical element that plays a critical role in cancer.Its function as a second messenger is crucial in various cellular pathways, including cell proliferation, differentiation and migration.
Disruptions in zinc homeostasis can lead to the development and aggressiveness of cancers.While some studies have presented contradictory results, there is a clear association between dysregulated levels of zinc importers (ZIPs) and exporters (ZnTs) and several types of cancer.However, the exact signaling mechanisms through which these transporters are involved in oncogenic processes remain to be fully elucidated, both at the specific cancer type level and potentially at the individual level, considering the strong interindividual heterogeneity in zinc protein expression levels.
The status of zinc and its associated proteins can serve as biomarkers for early detection, diagnosis and prognosis of cancer.Additionally, specific alterations in zinc metabolism in cancer present valuable targets for therapy.Down-regulation or overexpression of zinc-associated proteins have been used as rationales for developing innovative therapeutic strategies.Some compounds with high affinity for zinc show potential as treatments for certain cancers, although clinical trials investigating these compounds remain limited.
Furthermore, zinc is being explored as an alternative approach for cancer treatment, particularly within the emerging field of therapeutic nanoparticles.Zinc oxide nanoparticles (ZnO NPs) have demonstrated efficiency and selective toxicity against cancer cells.Ongoing studies utilizing ZnO NPs in cancer treatment are promising.In the future, zinc and its metabolism will undoubtedly continue to play a significant role in cancer diagnosis and the development of therapeutic strategies.(EMT), reduction in cell growth, invasion, migration and other tumorpromoting characteristics. 58,59,111ese inhibitory effects can be achieved through techniques such as siRNA, miRNA or knockout strategies. 42,43,68,112Another approach to modulate ZIP and ZnT zinc transporters is to target upstream or downstream proteins involved in their regulation and activity.For example, investigating the role of protein phosphorylation in regulating ZIP and ZnT activity could be a fruitful avenue for research. 155rthermore, zinc, like iron and copper, is a trace element.It would be interesting to explore combination treatments targeting zinc and other trace elements to enhance therapeutic effects or to utilize these trace elements collectively for early cancer diagnosis. 18,19,156erall, the review highlights the disrupted zinc metabolism in cancer, the potential of utilizing ZIP proteins as biomarkers and the strategies to target zinc transporter proteins for diagnostic and therapeutic purposes.Further research in this field holds great promise for advancing cancer detection and treatment approaches.

| FUTURE DIRECTIONS
Zinc metabolism is known to be disrupted in various cancers, with extensive literature documenting this phenomenon in prostate, pancreas and breast cancer.However, further experiments and studies are needed to gain a more accurate understanding of the mechanisms underlying the dysregulation of zinc transporter proteins in other types of cancer.Numerous ZIP proteins have been identified as altered proteins that play a fundamental role in tumorigenesis and cancer development.These findings provide valuable insights for exploring diagnostic and treatment options for associated cancers.The future direction in this field involves utilizing ZIP proteins as biomarkers for early cancer detection and developing highspecificity in vitro diagnostic devices targeting zinc-associated proteins.Targeting zinc transporter proteins represents a potential therapeutic approach for cancer treatment.Studies have shown that inhibition or upregulation of specific ZIP or ZnT proteins in certain cancers leads to the reversal of epithelial-mesenchymal transition The role and localization of Zn-associated proteins in cancer.
81A brain metastasis cell line derived from triple-negative breast cancer has shown increased Zn levels in the tumor microenvironment.Zn has the ability to enhance the tumorigenicity of breast cancer stem cells, and overexpression of ZIP4 also increases tumorigenicity.81Studies ha demonstrated varying levels of Zn in different breast cancer subtypes.Triple-negative breast cancer has the highest Zn levels, while estrogen and progesterone receptor-positive, HER2-negative breastT A B L E 2