Balancing between cuproplasia and copper-dependent cell death: molecular basis and clinical implications of ATOX1 in cancer

Abstract

Human antioxidant protein 1 (ATOX1) is an essential regulator of copper homeostasis in cells. By interacting with other proteins involved in controlling the intracellular levels of cuprous ions (Cu⁺), ATOX1 contributes to the import, export, and subcellular distribution of Cu⁺ as it functions within the CTR1-ATOX1-ATP7A/ATP7B axis. For this reason, ATOX1 plays a key role in preventing copper toxicity. Since copper ions have been shown to regulate the activity of a subset of other signaling proteins, ATOX1 can support cell proliferation, migration, and survival. Notably, ATOX1 is the only identified copper chaperone that has transcription factor activity. In this respect, CCND1, MDC1, NCF1, PPA2, and SOD3 have been experimentally validated as transcriptional targets of ATOX1 in distinct types of cells. The multifaceted actions of ATOX1 indicate that its dysregulation can lead to changes in the activity of crucial signaling pathways associated with diverse disorders, including cancer. Indeed, ATOX1 levels are frequently increased in cancer as demonstrated in multiple studies and supported by data available in GEPIA. ATOX1 has been implicated in cancer biology because of its role in the proliferation and metastatic spread of cancer cells and protection from oxidative stress. Additionally, ATOX1 may impact the drug response and resistance of cancer cells by influencing detoxification mechanisms as demonstrated for platinum-based therapies. In turn, the role of ATOX1 in the susceptibility of cancer cells to targeted therapies and immunotherapy remains elusive. This, however, should be a direction of further research considering the recent advances in understanding the complex role of copper in cancer cells, which can be associated with either protumorigenic effects (cuproplasia) or the induction of novel copper-dependent regulated cell death (cuproptosis) to combat cancer cells. Therefore, the disruption of ATOX1-mediated processes could be beneficial for the efficacy of anticancer therapies, although this possibility should be treated with caution because of the dual role of copper in cancer. Moreover, the prognostic value of ATOX1 expression for the clinical outcome of cancer patients needs to be clarified. In this review, we summarize the current state of knowledge about ATOX1 in cancer focusing on its molecular aspects and potential clinical implications.

Keywords: ATOX1; Cancer; Copper; Copper chaperone; Copper homeostasis; Cuproplasia; Cuproptosis; Oxidative stress.

Fig. 1

(a) Domain structure of ATOX1. The most important functional domains and their amino acid sequences are shown. (b) The major binding partners and their interactions with ATOX1 retrieved from STRING Protein-Protein Interaction Networks (https://string-db.org/) and described in the text. ATP7A/ATP7B, copper-transporting ATPase alpha/beta; CCS, copper chaperone for superoxide dismutase; COMMD1, COMM domain-containing protein 1; COX17, cyclooxygenase 17; MBD, metal-binding domain; NDUFA5, NADH: ubiquinone oxidoreductase subunit A5; NLS, nuclear localization sequence; SCO2, synthesis of cytochrome c oxidase 2; SLC31A1, solute carrier family 31 member 1; SOD, superoxide dismutase

Fig. 2

The contribution of ATOX1 to the regulation of cancer cell cycle progression. In the G1 phase of the cell cycle, ATOX can act as a transcription factor for CCND1 encoding cyclin D1, an important protein for regulating the transition from the G1 phase to the S phase of the cell cycle. p53 can inhibit the transcriptional activity of ATOX1, thereby downregulating CCDN1 expression. Additionally, p53 can upregulate the level of p21 protein that acts as an inhibitor of cyclin and downstream signaling with CDK4/6. ATOX1 can also be crucial for the transition between the G2 phase and the M phase of the cell cycle by stimulating the expression of the cyclin B1, which can also contribute to the activation of CDK1 by facilitating the transfer of copper ions from ATOX1 to CDK1. ATOX1 can also interact with APC triggering the degradation of proteins that regulate mitotic exit and entry into the G1 phase of the cell cycle. APC, anaphase-promoting complex; CDK, cyclin-dependent kinase

Fig. 3

The metastasis-promoting activities of ATOX1. In metastatic cancer cells, ATOX1 is predominantly localized in the nucleus. In addition, ATOX1 accumulates at the lamellipodial margins of migrating cancer cells. The ATOX1-ATP7A-LOX axis plays an important role in migrating cells and contributes to downstream pro-metastatic FAK/SRC signaling. COMMD3 may also be involved in the regulation of this axis. In addition, ATOX1 may be associated with microtubule guidance, actin network and adhesion site formation in migrating cells through interaction with MEMO1 and the MEMO-RhoA-mDia1 cascade. ATOX1 may also contribute to vascular remodeling and thus angiogenesis by interacting with the RAC1 protein in VSMC. COMMD3, COMM domain-containing protein 3; FAK1, focal adhesion kinase 1; LOXPP, a precursor of LOX; MEMO1, mediator of cell motility 1; RAC1, RAS-related C3 botulinum toxin substrate 1; RhoA, Ras homolog family member A; VSMC, vascular smooth muscle cells

Fig. 4

(a) Transcript levels of ATOX1 were retrieved from Gene Expression Profiling Integrative Analysis (GEPIA) and shown for different types of cancer. Cancers with significantly higher ATOX1 mRNA levels compared with normal cells are marked in red. n – number of samples (b) Overall survival of patients with cancers marked in red in panel (a). The median level of ATOX1 mRNA was used as a group cutoff. ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; DLBC, diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma