Role of the Human Cytochrome B561 Family in Iron Metabolism and Tumors (Review)

Overview

Journal Oncol Lett

Date 2025 Jan 13

PMID 39802312

Authors

Xiaofeng Zhou

Zheng An

Hao Lei

Hongyuan Liao

Xinjian Guo

Affiliations

Soon will be listed here.

Abstract

The human cytochrome b561 (hCytb561) family consists of electron transfer transmembrane proteins characterized by six conserved α-helical transmembrane domains and two β-type heme cofactors. These proteins contribute to the regulation of iron metabolism and numerous different physiological and pathological processes by recycling ascorbic acid and maintaining iron reductase activity. Key members of this family include cytochrome b561 (CYB561), duodenal CYB561 (Dcytb), lysosomal CYB561 (LCytb), stromal cell-derived receptor 2 (SDR2) and 101F6, which are widely expressed in human tissues and participate in the pathogenesis of several diseases and tumors. They are associated with the promotion or inhibition of tumor growth and progression in various malignancies and are potential therapeutic targets for malignant tumors. The present review summarizes the existing literature regarding the structure of the Cytb561 family, the basic functional characteristics of hCytb561 family members, and the roles of the CYB561, Dcytb, LCytb, SDR2 and 101F6 in various diseases and tumors.

References

Asard H, Horemans N, Caubergs R . Transmembrane electron transport in ascorbate-loaded plasma membrane vesicles from higher plants involves a b-type cytochrome. FEBS Lett. 1992; 306(2-3):143-6. DOI: 10.1016/0014-5793(92)80986-q. View

Holt R, Subramanian G, Halpern A, Sutton G, Charlab R, Nusskern D . The genome sequence of the malaria mosquito Anopheles gambiae. Science. 2002; 298(5591):129-49. DOI: 10.1126/science.1076181. View

Nakanishi N, Takeuchi F, Tsubaki M . Histidine cycle mechanism for the concerted proton/electron transfer from ascorbate to the cytosolic haem b centre of cytochrome b561: a unique machinery for the biological transmembrane electron transfer. J Biochem. 2007; 142(5):553-60. DOI: 10.1093/jb/mvm181. View

Kawabata H . Transferrin and transferrin receptors update. Free Radic Biol Med. 2018; 133:46-54. DOI: 10.1016/j.freeradbiomed.2018.06.037. View

Rychtarcikova Z, Lettlova S, Tomkova V, Korenkova V, Langerova L, Simonova E . Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism. Oncotarget. 2016; 8(4):6376-6398. PMC: 5351639. DOI: 10.18632/oncotarget.14093. View

Torti S, Torti F . Iron and Cancer: 2020 Vision. Cancer Res. 2020; 80(24):5435-5448. PMC: 8118237. DOI: 10.1158/0008-5472.CAN-20-2017. View

Tao B, Shi J, Shuai S, Zhou H, Zhang H, Li B . CYB561D2 up-regulation activates STAT3 to induce immunosuppression and aggression in gliomas. J Transl Med. 2021; 19(1):338. PMC: 8351164. DOI: 10.1186/s12967-021-02987-z. View

Srivastava M . Xenopus cytochrome b561: molecular confirmation of a general five transmembrane structure and developmental regulation at the gastrula stage. DNA Cell Biol. 1996; 15(12):1075-80. DOI: 10.1089/dna.1996.15.1075. View

Boult J, Roberts K, Brookes M, Hughes S, Bury J, Cross S . Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res. 2008; 14(2):379-87. DOI: 10.1158/1078-0432.CCR-07-1054. View

10.

Linton K, Hey Y, Saunders E, Jeziorska M, Denton J, Wilson C . Acquisition of biologically relevant gene expression data by Affymetrix microarray analysis of archival formalin-fixed paraffin-embedded tumours. Br J Cancer. 2008; 98(8):1403-14. PMC: 2361698. DOI: 10.1038/sj.bjc.6604316. View

11.

. Analysis of the genome sequence of the flowering plant Arabidopsis thaliana. Nature. 2000; 408(6814):796-815. DOI: 10.1038/35048692. View

12.

Lane D, Richardson D . The active role of vitamin C in mammalian iron metabolism: much more than just enhanced iron absorption!. Free Radic Biol Med. 2014; 75:69-83. DOI: 10.1016/j.freeradbiomed.2014.07.007. View

13.

Vargas J, Herpers B, McKie A, Gledhill S, McDonnell J, van den Heuvel M . Stromal cell-derived receptor 2 and cytochrome b561 are functional ferric reductases. Biochim Biophys Acta. 2003; 1651(1-2):116-23. DOI: 10.1016/s1570-9639(03)00242-5. View

14.

Asard H, Barbaro R, Trost P, Berczi A . Cytochromes b561: ascorbate-mediated trans-membrane electron transport. Antioxid Redox Signal. 2012; 19(9):1026-35. PMC: 3763232. DOI: 10.1089/ars.2012.5065. View

15.

Takeuchi F, Kobayashi K, Tagawa S, Tsubaki M . Ascorbate inhibits the carbethoxylation of two histidyl and one tyrosyl residues indispensable for the transmembrane electron transfer reaction of cytochrome b561. Biochemistry. 2001; 40(13):4067-76. DOI: 10.1021/bi002240x. View

16.

Yang X, Zhao Y, Shao Q, Jiang G . Cytochrome b561 Serves as a Potential Prognostic Biomarker and Target for Breast Cancer. Int J Gen Med. 2022; 14:10447-10464. PMC: 8722309. DOI: 10.2147/IJGM.S338878. View

17.

Morales M, Xue X . Targeting iron metabolism in cancer therapy. Theranostics. 2021; 11(17):8412-8429. PMC: 8344014. DOI: 10.7150/thno.59092. View

18.

Lane D, Robinson S, Czerwinska H, Bishop G, Lawen A . Two routes of iron accumulation in astrocytes: ascorbate-dependent ferrous iron uptake via the divalent metal transporter (DMT1) plus an independent route for ferric iron. Biochem J. 2010; 432(1):123-32. DOI: 10.1042/BJ20101317. View

19.

Galy B, Conrad M, Muckenthaler M . Mechanisms controlling cellular and systemic iron homeostasis. Nat Rev Mol Cell Biol. 2023; 25(2):133-155. DOI: 10.1038/s41580-023-00648-1. View

20.

Lee H, Li C, Li W, Hsu Y, Yeh H, Ke H . Identification of potential genes in upper tract urothelial carcinoma using next-generation sequencing with bioinformatics and in vitro analyses. PeerJ. 2021; 9:e11343. PMC: 8086570. DOI: 10.7717/peerj.11343. View