Abstract
Trace metal homeostasis is increasingly recognized as a reflection of cellular metabolism and redox balance. This study applies high-precision copper isotope and elemental ratio analysis to human serum to investigate how prostate cancer alters systemic metal regulation. Using multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) adapted from geochemical applications, we quantified copper isotope fractionation and Cu/Zn ratios across disease stages. Patients with localized or newly metastatic prostate cancer exhibited isotopically heavier serum copper compared to healthy controls, while advanced, castration-resistant disease showed higher copper concentrations, lower zinc levels, and elevated Cu/Zn ratios. Together, these findings suggest that prostate cancer-associated alterations in copper and zinc homeostasis may reflect modulation by sex steroid-dependent physiological states. They also demonstrate the sensitivity of MC-ICP-MS in detecting subtle isotopic shifts in biological samples and establish its value as a tool for characterizing metabolic and redox alterations in prostate cancer.
Similar content being viewed by others
Data availability
All deidentified data reported in this paper will be shared by the lead contact upon request. This paper does not report original code. Requests for further information and resources should be directed to and will be fulfilled by the lead contact, Robert Raad (raadr@usc.edu).
References
Bian, X. et al. Distribution and Cycling of Nickel and Nickel Isotopes in the Pacific Ocean. Geophys. Res. Lett. 51 (16), e2024GL111115. https://doi.org/10.1029/2024GL111115 (2024). (accessed 2025/10/13).
Yang, S. C. et al. A new anion exchange purification method for Cu stable isotopes in blood samples. Anal. Bioanal. Chem. 411 (3), 765–776. https://doi.org/10.1007/s00216-018-1498-4 (2019).
Collins, J. F. Chapter Nine - Copper nutrition and biochemistry and human (patho)physiology. In Advances in Food and Nutrition Research, Eskin, N. A. M. Ed.; Vol. 96; Academic, ; 311–364. (2021).
Robinson, N. J. & Winge, D. R. Copper metallochaperones. Annu. Rev. Biochem. 79 (1), 537–562. https://doi.org/10.1146/annurev-biochem-030409-143539 (2010).
Albarede, F. et al. Medical applications of Cu, Zn, and S isotope effects. Metallomics 8 (1), 156–117. https://doi.org/10.1039/c5mt00316d (2016).
Kerkadi, A. et al. The association between zinc and copper circulating levels and cardiometabolic risk factors in adults: A study of qatar biobank data. Nutrients 13 (8), 2729. https://doi.org/10.3390/nu13082729 (2021).
Télouk, P. et al. Copper isotope effect in serum of cancer patients. A pilot study. Metallomics 7 (2), 299–308. https://doi.org/10.1039/c4mt00269e (2015). From NLM.
Kazi Tani, L. S. et al. Copper Isotopes and Copper to Zinc Ratio as Possible Biomarkers for Thyroid Cancer. Front. Med. 8, 698167–698167. https://doi.org/10.3389/fmed.2021.698167 (2021).
Toubhans, B. et al. Cu isotope ratios are meaningful in ovarian cancer diagnosis. J. Trace Elem. Med Biol. 62, 126611–126611. https://doi.org/10.1016/j.jtemb.2020.126611 (2020).
Hastuti, A. A. M. B. et al. Cu and Zn isotope ratio variations in plasma for survival prediction in hematological malignancy cases. Sci. Rep. 10 (1), 16389. https://doi.org/10.1038/s41598-020-71764-7 (2020).
Van Campenhout, S. et al. Lighter serum copper isotopic composition in patients with early non-alcoholic fatty liver disease. BMC Res. Notes. 13 (1), 225. https://doi.org/10.1186/s13104-020-05069-3 (2020).
Bondanese, V. P. et al. Hypoxia induces copper stable isotope fractionation in hepatocellular carcinoma, in a HIF-independent manner. Metallomics 8 (11), 1177–1184. https://doi.org/10.1039/C6MT00102E (2016).
Costas-Rodríguez, M. et al. Isotopic analysis of Cu in blood serum by multi-collector ICP-mass spectrometry: a new approach for the diagnosis and prognosis of liver cirrhosis?†. Metallomics 7 (3), 491–498. https://doi.org/10.1039/c4mt00319e (2015). (accessed 7/12/2024).
Miaou, E. & Tissot, F. L. H. Copper isotope ratios in serum do not track cancerous tumor evolution, but organ failure. Metallomics 15 (11). https://doi.org/10.1093/mtomcs/mfad060 (2023). From NLM.
Lauwens, S., Costas-Rodríguez, M., Van Vlierberghe, H. & Vanhaecke, F. Cu isotopic signature in blood serum of liver transplant patients: a follow-up study. Sci. Rep. 6 (1), 30683. https://doi.org/10.1038/srep30683 (2016).
ji, K. et al. Significance of trace elements copper and zinc change in the serum of patients with prostate cancer. 21, 9–10. (2007).
Ghellai, I. E., Dennouni-Medjati, Y. H. N. & Rouabhi, H. Majda Dali-Sahi. Serum Levels of Zinc and Copper and Cu/Zn Ratio in Algerian Prostate Cancer Patients. J. Chem. Health Risks. 14 (6), 198–205 (2024).
Feng, Y. et al. Serum copper and zinc levels in breast cancer: A meta-analysis. J. Trace Elem. Med Biol. 62, 126629. https://doi.org/10.1016/j.jtemb.2020.126629 (2020).
Ribeiro, S. M. et al. Copper-Zinc ratio and nutritional status in colorectal cancer patients during the perioperative period. Acta Cir. Bras. 31 (Suppl 1), 24–28. https://doi.org/10.1590/s0102-86502016001300006 (2016). From NLM.
Shishido, S. N. et al. Preanalytical Variables for the Genomic Assessment of the Cellular and Acellular Fractions of the Liquid Biopsy in a Cohort of Breast Cancer Patients. J. Mol. Diagn. 22 (3), 319–337. https://doi.org/10.1016/j.jmoldx.2019.11.006 (2020). From NLM.
Rodríguez-Lee, M. et al. Effect of Blood Collection Tube Type and Time to Processing on the Enumeration and High-Content Characterization of Circulating Tumor Cells Using the High-Definition Single-Cell Assay. Arch. Pathol. Lab. Med. 142 (2), 198–207. https://doi.org/10.5858/arpa.2016-0483-OA (2018). From NLM.
Higa, N. et al. Liquid Biopsy Profiling with Multiple Tests in Patients with Metastatic Breast Cancer. J. Mol. Pathol. 5, 199–214 (2024).
Takano, S. et al. A simple and rapid method for isotopic analysis of nickel, copper, and zinc in seawater using chelating extraction and anion exchange. Anal. Chim. Acta. 967, 1–11. https://doi.org/10.1016/j.aca.2017.03.010 (2017).
Kyriakopoulos, C. E. et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J. Clin. Oncol. 36 (11), 1080–1087. https://doi.org/10.1200/jco.2017.75.3657 (2018). From NLM.
Berthold, D. R. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J. Clin. Oncol. 26 (2), 242–245. https://doi.org/10.1200/jco.2007.12.4008 (2008). From NLM.
Stensland, K. D. et al. National Long-term Survival Estimates After Radical Prostatectomy for Prostate Cancer. Urology 184, 135–141. https://doi.org/10.1016/j.urology.2023.10.018 (2024). From NLM.
Bengtsson, Y. et al. Serum copper, zinc and copper/zinc ratio in relation to survival after breast cancer diagnosis: A prospective multicenter cohort study. Redox Biol. 63, 102728–102728. https://doi.org/10.1016/j.redox.2023.102728 (2023).
Otsuka, T., Hamada, A., Iguchi, K., Usui, S. & Hirano, K. Suppression of metallothionein 3 gene expression by androgen in LNCaP prostate cancer cells. Biomed. Rep. 1 (4), 614–618. https://doi.org/10.3892/br.2013.107 (2013). From NLM.
Tohyama, C. et al. Testosterone-dependent induction of metallothionein in genital organs of male rats. Biochem J 317 (Pt 1) (Pt 1), 97–102. DOI: 10.1042/bj3170097 From NLM. (1996).
Thomas, P., Pang, Y., Dong, J. & Berg, A. H. Identification and characterization of membrane androgen receptors in the ZIP9 zinc transporter subfamily: II. Role of human ZIP9 in testosterone-induced prostate and breast cancer cell apoptosis. Endocrinology 155 (11), 4250–4265. https://doi.org/10.1210/en.2014-1201 (2014). From NLM.
Zhang, L. et al. Testosterone suppresses oxidative stress via androgen receptor-independent pathway in murine cardiomyocytes. Mol. Med. Rep. 4 (6), 1183–1188. https://doi.org/10.3892/mmr.2011.539 (2011). From NLM.
Denoyer, D. et al. Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution. Oncotarget 7 (24), 37064–37080. https://doi.org/10.18632/oncotarget.9245 (2016). From NLM.
Safi, R. et al. Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 74 (20), 5819–5831. https://doi.org/10.1158/0008-5472.Can-13-3527 (2014). From NLM.
Lubiński, J. et al. Serum Essential Elements and Survival after Cancer Diagnosis. Nutrients 15 (11). DOI: 10.3390/nu15112611 From NLM. (2023).
Acknowledgements
We are grateful to the patients and their caregivers for their participation and trust. We thank the clinical teams and research consent staff for their essential support in patient recruitment and sample collection. We acknowledge the contributions of the blood processing team and data infrastructure team. We extend our gratitude to Dr. Mohamed Kamal for his thoughtful review and editorial comments on our manuscript.
Author information
Authors and Affiliations
Contributions
Author contributions conceptualization, RJR, SCY, JN, AK, SNS, WMB, AJW, PK, SGJ computational analysis, RJR data curation and formal analysis, SCY data visualization, RJR investigation, RJR, SCY, JLW, JJR, JN writing—original draft preparation, RJR, JLW, JJR, JN, PK writing—review and editing, RJR, SCY, JLW, JJR, JN, AK, SNS, WMB, AJW, PK, SGJ project administration, JN, AK, SNS, WMB, AJW, PK, SGJ funding acquisition, SGJ, PK, AK subject recruitment, PK, JN, AK resources, HN, PK, SGJ validation, RR, SCY, JLW, JJR, JN, AK, SNS, WMB, AJW, PK, SGJ All authors have read and agreed to the published version of the manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Raad, R.J., Yang, SC., Wang, J.L. et al. Copper isotope fractionation and copper-to-zinc ratios reveal altered metal homeostasis in prostate cancer. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46224-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-46224-3
