Copper metabolism as a unique vulnerability in cancer

Shanbhag, Vinit; Gudekar, Nikita; Jasmer, Kimberly J.; Papageorgiou, Christos; Singh, Kamal; Petris, Michael J.

doi:10.1016/j.bbamcr.2020.118893

Cited by 252 publications

(215 citation statements)

References 202 publications

Supporting

Mentioning

213

Contrasting

Unclassified

Order By: Relevance

“…Cancer cells require higher Cu resources for e.g., the Warburg effect—an early metabolic switch by which cancer cells produce energy via glycolysis instead of mitochondrial oxidative phosphorylation. Moreover, increased Cu concentration is needed to potentiate the activity of cupro-enzymes like lysyl oxidase (LOX), superoxide dismutase (SOD), and cytochrome-c-oxidase (COX) as well as some molecular pathways which support cancer cell proliferation and survival, like mitogen-activated protein (MAP) kinases and autophagic ULK1/2 kinases [ 15 ]. Additionally, Cu and Zn have specific and different activities.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, although we performed our analysis using multivariable Cox proportional hazard analysis, we cannot rule out other residual confounding variables and that the obtained effects were not completely adjusted by other factors. Actually, circulating Cu and Zn status has been shown to be associated with dietary intakes, disturbances in redox status, immune system, and metabolic derangements [ 12 , 15 , 46 , 63 ]. In this study, it was however not possible to control all factors influencing Cu and Zn status such as diet, lifestyle, and clinical parameters; therefore, further studies should be performed in a more homogenous group of lung cancer patients, or analyses should also be adjusted for the above-mentioned data to better associate the impact of circulating Cu and Zn status on predicting mortality in lung cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…The Cu–Zn balance is often disturbed during systemic breakdown of whole body homeostasis due to, e.g., malabsorption, excessive excretion, abnormal requirements, inflammatory processes, and redox imbalance related to chronic illness, e.g., cancer [ 13 , 14 ]. Additionally, demand for Cu is elevated in proliferating cancer cells relative to other tissues; thus, metabolic vulnerability can be exploited by controlling Cu availability during cancer progression [ 15 ]. Although mortality prediction based on serum Cu and Zn status has been studied in cancers [ 16 , 17 ], to date no data on the role of Cu and Zn disturbances in predicting the mortality of lung cancer patients have been presented.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Serum and Whole Blood Cu and Zn Status in Predicting Mortality in Lung Cancer Patients

et al. 2020

View full text Add to dashboard Cite

Alterations in circulating Cu and Zn are negative predictors of survival in neoplastic patients and are known during lung cancer. However, no data on predicting mortality of lung cancer patients based on the level of these elements in the blood have been presented to date. The aims of this prospective cohort study were as follows: (i) To evaluate the disturbances in serum and whole blood Cu and Zn, (ii) to assess the relationships between serum and whole blood Cu and Zn status and clinical, sociodemographic, and nutritional data, and (iii) to investigate the association of Cu and Zn status with all-cause mortality in lung cancer. Naïve-treatment lung cancer patients (n = 167) were characterized in terms of sociodemographic, clinical, and anthropometric data and dietary intake and compared with sex-matched control subjects (n = 48). Whole blood and serum Cu and Zn status was determined by atomic absorption spectrometry. Cox proportional hazards models adjusted for multiple confounders/mediators were used to estimate the association between all-cause death and Cu and Zn status. Sex, cardiovascular disease, chronic obstructive pulmonary disease, clinical stage, and hemoglobin, platelet, and glucose concentrations significantly differentiated Cu and Zn status. All-cause mortality in lung cancer patients was positively associated with serum Cu levels, Cu:Zn ratio, and whole blood Zn levels. However, an advanced clinical stage of disease was the strongest predictor of all-cause mortality. Circulatory status of Cu and Zn might be included in routine clinical characteristics of patients with lung cancer patients as additional prognostic variables, but only after further more detail studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Serum and Whole Blood Cu and Zn Status in Predicting Mortality in Lung Cancer Patients

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Excessive copper ions (Cu(II)) may generate ROS, which mediates oxidative damage to lipids, proteins, and DNA. Multiple types of tumors (e.g., breast and colorectal cancers) have aberrantly elevated copper levels, which promote tumor progression by increasing cell proliferation and stimulating angiogenesis and metastasis ( Denoyer et al, 2015 ; Li, 2020 ; Shanbhag et al, 2020 ). This abnormal copper pathway in cancer can be targeted by two strategies.…”

Section: Copper Complexes As Ups Inhibitors In Cancer Treatmentmentioning

confidence: 99%

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

Chen

Dou

Liu

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

Characterizing mechanisms of protein homeostasis, a process of balancing between protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The ubiquitin–proteasome system (UPS) is a well-studied mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or aging proteins, thereby maintaining quality and quantity of cellular proteins. The UPS is composed of multiple components, including a series of enzymes (E1, E2, E3, and deubiquitinase [DUB]) and 26S proteasome (19S regulatory particles + 20S core particle). An impaired UPS pathway is involved in multiple diseases, including cancer. Several proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are approved to treat patients with certain cancers. However, their applications are limited by side effects, drug resistance, and drug–drug interactions observed in their clinical processes. To overcome these shortcomings, alternative UPS inhibitors have been searched for in many fields. Copper complexes (e.g., CuET, CuHQ, CuCQ, CuPDTC, CuPT, and CuHK) are found to be able to inhibit a core component of the UPS machinery, such as 20S proteasome, 19S DUBs, and NPLOC4/NPL4 complex, and are proposed to be one class of metal-based anticancer drugs. In this review, we will summarize functions and applications of copper complexes in a concise perspective, with a focus on connections between the UPS and cancer.

show abstract

“…This review centers on function and biogenesis of copper-dependent enzymes, which are activated/matured by copper loading at various sites in cells, which relates to protein trafficking. Cellular copper homeostasis is extensively covered in other reviews, e.g., [ 10 , 11 , 12 ], and will not be discussed here unless pertinent for understanding activation of copper enzymes.…”

Section: Copper Enzymesmentioning

confidence: 99%

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

Horn

Wittung-Stafshede

2021

Biomedicines

View full text Add to dashboard Cite

Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients.

show abstract

Copper metabolism as a unique vulnerability in cancer

Cited by 252 publications

References 202 publications

Serum and Whole Blood Cu and Zn Status in Predicting Mortality in Lung Cancer Patients

Serum and Whole Blood Cu and Zn Status in Predicting Mortality in Lung Cancer Patients

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

Contact Info

Product

Resources

About