STEAP Proteins: From Structure to Applications in Cancer Therapy

Abstract

The human 6-transmembrane epithelial antigen of prostate (STEAP) family comprises STEAP1, STEAP2, STEAP3, and STEAP4. All of these proteins are unique to mammals and share an innate activity as metalloreductases, indicating their importance in metal metabolism. Overall, they participate in a wide range of biologic processes, such as molecular trafficking in the endocytic and exocytic pathways and control of cell proliferation and apoptosis. STEAP1 and STEAP2 are overexpressed in several types of human cancers, namely prostate, bladder, colon, pancreas, ovary, testis, breast, cervix, and Ewing sarcoma, but their clinical significance and role in cancer cells are not clear. Still, their localization in the cell membrane and differential expression in normal and cancer tissues make STEAP proteins potential candidates as biomarkers of several cancers, as well as potential targets for new immunotherapeutic strategies for disease attenuation or treatment. This review brings together the current knowledge about each STEAP protein, giving an overview of the roles of this family of proteins in human physiology and disease, and analyzes their potential as immunotherapeutic agents in cancer research. Mol Cancer Res; 10(5); 573-87. Ó2012 AACR. IntroductionThe 6-transmembrane epithelial antigen of prostate (STEAP) family of proteins includes 4 members, named 6-transmembrane epithelial antigen of prostate 1 to 4 (STEAP1-STEAP4). They all have in common a 6-transmembrane domain, a COOH-terminal domain with significant homology to the yeast FRE family of b-type cytochrome metalloreductases, and an N-terminal with homology to the archaeal and bacterial F 420 H 2 :NADP

The Crystal Structure of Six-transmembrane Epithelial Antigen of the Prostate 4 (Steap4), a Ferri/Cuprireductase, Suggests a Novel Interdomain Flavin-binding Site

“…This N-terminal domain works in conjunction with the C-terminal transmembrane domain to confer cell surface ferric and cupric reductase activity to these larger Steap2-4 family members (2,3). Steap1 and Steap2 are highly overexpressed in a number of different human cancers (prostate, bladder, colon, pancreas, ovary, testis, breast, cervix, and Ewing sarcoma) (4 -6); however, their roles in both normal and cancer cells are not well understood (7). In contrast, Steap3 is the only family member for which a clear physiological role has been demonstrated.…”

In-silico analysis of non-synonymous-SNPs of STEAP2: To provoke the progression of prostate cancer

“…In several types of human cancers such as prostate, cervix, ovary, testis, breast, colon, pancreas, iEwing sarcoma and bladder, the expression of STEAP1 and STEAP2 is significantly high. The expression of this family is different in normal and cancerous tissue making them possible candidate for the therapeutic strategies [18]. Previous studies have shown that the expression of STEAP2 is 10 times higher in prostate cancer.…”

“…In PCa, MMPs -2, -7, -9, -13 and -14 have been shown to be involved and their over-expression promotes PCa growth and metastasis [2]. In early endosomes and the TGN Trans Golgi network STEAP2 can also be found and it acts as a receptor for both exogenous and endogenous ligands or as regulator of protein delivery and sorting mechanisms [2,18].…”

Handling of Copper and Copper Oxide Nanoparticles by Astrocytes

“…One metal-reductase involved could be Dcytb, a cytochrome b family homologue, which has been shown to be expressed in cultured astrocytes [60,66]. Astrocytes also contain the mRNAs of proteins of the 6-transmembrane epithelial antigen of prostate (Steap) family, suggesting that astrocytes may also contain the respective proteins which have extracellular cuprireductase activity [67][68][69].…”