Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets

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Abstract

Zinc metabolism at the cellular level is critical for many biological processes in the body. A key observation is the disruption of cellular homeostasis, often coinciding with disease progression. As an essential factor in maintaining cellular equilibrium, cellular zinc has been increasingly spotlighted in the context of disease development. Extensive research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells, despite its low tissue concentration. This has led to a growing body of literature investigating zinc’s cellular metabolism, particularly the functions of zinc transporters and storage mechanisms during cancer progression. Zinc transportation is under the control of two major transporter families: SLC30 (ZnT) for the excretion of zinc and SLC39 (ZIP) for the zinc intake. Additionally, the storage of this essential element is predominantly mediated by metallothioneins (MTs). This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression, with a special focus on cancer. We also compile a summary of clinical trials involving zinc ions. Given the main localization of zinc transporters at the cell membrane, the potential for targeted therapies, including small molecules and monoclonal antibodies, offers promising avenues for future exploration.

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Cancer statistics, 2023

Rebecca L Siegel, Kimberly D Miller, Nikita Sandeep Wagle … (2023)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.

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Pan-cancer analysis of whole genomes

Peter J Campbell, Gad Getz, Jan O. Korbel … (2020)

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

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Cancer drug resistance: an evolving paradigm.

Caitriona Holohan, Sandra Van Schaeybroeck, Daniel Longley … (2013)

Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.

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Author and article information

Contributors

Wei Kang:

ORCID: http://orcid.org/0000-0002-4651-677X

weikang@cuhk.edu.hk

Ka Fai To:

ORCID: http://orcid.org/0000-0003-4919-3707

kfto@cuhk.edu.hk

Journal

Journal ID (nlm-ta): Signal Transduct Target Ther

Journal ID (iso-abbrev): Signal Transduct Target Ther

Title: Signal Transduction and Targeted Therapy

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 2095-9907

ISSN (Electronic): 2059-3635

Publication date (Electronic): 3 January 2024

Publication date PMC-release: 3 January 2024

Publication date Collection: 2024

Volume: 9

Electronic Location Identifier: 6

Affiliations

[1 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, , Prince of Wales Hospital, The Chinese University of Hong Kong, ; Hong Kong, China

[2 ]State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, ( https://ror.org/00t33hh48) Hong Kong, China

[3 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, CUHK-Shenzhen Research Institute, , The Chinese University of Hong Kong, ; Shenzhen, China

[4 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Department of Pathology, Nanfang Hospital and Basic Medical College, , Southern Medical University, Guangdong Province Key Laboratory of Molecular Tumor Pathology, ; Guangzhou, China

[5 ]GRID grid.443573.2, ISNI 0000 0004 1799 2448, Institute of Biomedical Research, , Taihe Hospital, Hubei University of Medicine, ; Shiyan, China

[6 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Pediatrics, , The Chinese University of Hong Kong, ; Hong Kong, China

[7 ]GRID grid.10784.3a, ISNI 0000 0004 1937 0482, Department of Medicine and Therapeutics, , The Chinese University of Hong Kong, ; Hong Kong, China

Author information

Bonan Chen http://orcid.org/0000-0002-2430-7934

Kam Tong Leung http://orcid.org/0000-0002-7695-2513

Kwok Wai Lo http://orcid.org/0000-0002-3488-6124

Jun Yu http://orcid.org/0000-0001-5008-2153

Wei Kang http://orcid.org/0000-0002-4651-677X

Ka Fai To http://orcid.org/0000-0003-4919-3707

Article

Publisher ID: 1679

DOI: 10.1038/s41392-023-01679-y

PMC ID: 10761908

PubMed ID: 38169461

SO-VID: 84e196de-5ed6-4546-990f-5e1e19749cfe

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 27 May 2023

Date revision received : 15 September 2023

Date accepted : 10 October 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82272990

Award Recipient : Wei Kang

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Keywords: tumour angiogenesis,cancer therapy,cell biology

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Keywords: tumour angiogenesis, cancer therapy, cell biology

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Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets

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Evolutionary Cell Biology

Most cited references 703

Cancer statistics, 2023

Pan-cancer analysis of whole genomes

Cancer drug resistance: an evolving paradigm.

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Most referenced authors 9,476