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Cancer is a global health issue that impairs the life quality of patients and origins thousands of deaths annually worldwide. Six-transmembrane epithelial antigen of the prostate (STEAP1) was identified to be overexpressed in several types of cancers, namely in prostate cancer (PCa). Considering its secondary structure, associated with its location in the cell membrane, has been suggested a role in intercellular communication between tumour cells. Taking into account its high specificity and overexpression in human cancers, STEAP1 is nowadays a promising candidate to be imposed as a therapeutic target. Several strategies have been developed during the last few years for targeting STEAP1, including antibody-drug conjugates, monoclonal antibodies (mAbs), DNA vaccines and small noncoding RNAs (ncRNAs). This review presents the current knowledge about STEAP1 protein expression in human tissues, its biochemical properties and targeting strategies with the purpose to evaluate its potential as therapeutic agent for cancer.

BACKGROUND Regucalcin (RGN) is a calcium (Ca2+)-binding protein underexpressed in prostate adenocarcinoma comparatively to non-neoplastic prostate or benign prostate hyperplasia cases. Moreover, RGN expression is negatively associated with the cellular differentiation of prostate adenocarcinoma, suggesting that loss of RGN may be associated with tumor onset and progression. However, the RGN actions over the control of prostate cell growth have not been investigated. METHODS Androgens are implicated in the promotion of prostate cell proliferation, thus we studied the in vivo effect of androgens on RGN expression in rat prostate. The role of RGN modulating cell proliferation and apoptotic pathways in rat prostate was investigated using transgenic animals (Tg-RGN) overexpressing the protein. RESULTS In vivo stimulation with 5α-dihydrotestosterone (DHT) down-regulated RGN expression in rat prostate. Cell proliferation index and prostate weight were reduced in Tg-RGN, which was concomitant with altered expression of cell-cycle regulators. Tg-RGN presented diminished expression of the oncogene H-ras and increased expression of cell-cycle inhibitor p21. Levels of anti-apoptotic Bcl-2, as well as the Bcl-2/Bax protein ratio were increased in prostates overexpressing RGN. Both caspase-3 expression and enzyme activity were decreased in the prostates of Tg-RGN. CONCLUSIONS Overexpression of RGN resulted in inhibition of cell proliferation and apoptotic pathways, which demonstrated its role maintaining prostate growth balance. Thus, deregulation of RGN expression may be an important event favoring the development of prostate cancer. Moreover, the DHT effect down-regulating RGN expression in rat prostate highlighted for the importance of this protein in prostatic physiology. Prostate 74:1189–1198, 2014. © 2014 Wiley Periodicals, Inc.

The development of prostate cancer (PCa) is intimately associated with the hormonal environment, and the sex steroids estrogens have been implicated in prostate malignancy. However, if some studies identified estrogens as causative agents of PCa, others indicated that these steroids have a protective role counteracting prostate overgrowth. The tyrosine kinase receptor c-KIT and its ligand, the stem cell factor (SCF), have been associated with the control of cell proliferation/apoptosis and prostate carcinogenesis, and studies show that estrogens regulate their expression in different tissues, though, in the case of prostate this remains unknown. The present study aims to evaluate the role of 17β-estradiol (E2) in regulating the expression of SCF/c-KIT in human prostate cell lines and rat prostate, and to investigate the consequent effects on prostate cell proliferation and apoptosis. qPCR, Western Blot, and immuno(cito)histochemistry analysis showed that E2-treatment decreased the expression of SCF and c-KIT both in human prostate cells and rat prostate. Furthermore, the diminished expression of SCF/c-KIT was underpinned by the diminished prostate weight and reduced proliferation index. On the other hand, the results of TUNEL labelling, the increased activity of caspase-3, and the augmented expression of caspase-8 and Fas system in the prostate of E2-treated animals indicated augmented apoptosis in response to E2. The obtained results demonstrated that E2 down-regulated the expression of SCF/c-KIT system in prostate cells, which was associated with antiproliferative and proapoptotic effects. Moreover, these findings support the protective role of estrogens in PCa and open new perspectives on the application of estrogen-based therapies.

BACKGROUND STEAP1 is over-expressed in several types of tumors, especially prostate cancer, where it is localized in the plasma membrane of epithelial cells, at cell–cell junctions. Its role in prostate carcinogenesis and its regulation in prostate cells remain unknown. Therefore, we propose to study the effect of sex hormones in the regulation of STEAP1 expression in prostate cells in vitro and in vivo. METHODS LNCaP prostate cells were incubated with fetal bovine serum (FBS), charcoal-stripped FBS (CS-FBS), 5α-dihydrotestosterone (DHT), and 17β-estradiol (E2) for different periods of stimulation. In addition, adult male Wistar rats were castrated and treated with DHT and E2. The levels of STEAP1 in response to treatments were analyzed by real-time PCR, Western blot, and immunohistochemistry. RESULTS The treatment of LNCaP cells with DHT or E2 induces a down-regulation of STEAP1 expression, while incubation with CS-FBS has the opposite effect. Experiments using inhibitors of androgen and estrogen receptor (AR and ER) showed that down-regulation of STEAP1 is AR-dependent, but ER-independent. However, the mediation of six transmembrane epithelial antigen of the prostate 1 (STEAP1) expression by AR seems to be dependent of de novo protein synthesis. In vivo studies showed that castrated rats express higher levels of STEAP1 protein when compared to intact rats, an effect reversed by DHT or E2 replacement. CONCLUSIONS STEAP1 is down-regulated by DHT and E2 in LNCaP cells and in rat prostate. Prostate 73: 605–613, 2013. © 2012 Wiley Periodicals, Inc.

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. ©2012 AACR.

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) was identified a gene overexpressed in human prostate cancer. It is localized in cell junctions of epithelial cells, and its structure with six transmembrane domains suggests that it may act as a membrane channel or transporter protein in tight junctions [1]. Although STEAP1 expression seems to be up-regulated in prostate cancer, the clinical significance of this finding remains to be clarified. Moreover, STEAP1 is more expressed in LNCaP than in PC3, suggesting that androgens may regulate its expression. Therefore, the goals of this experimental work were: i) to evaluate if STEAP1 expression correlates with clinical reports from patients; ii) to analyze if STEAP1 is regulated by 5α-dihydrotestosterone (DHT) in vitro and in vivo. Immunohistochemical analysis shows that STEAP1 expression is mainly expressed in epithelial cells. Analysis of STEAP1 immunoreactivity in prostate cancer is underway. In vivo results demonstrated that castration increases STEAP1 protein expression when compared to intact rats, and treatment with DHT abrogates the effect of castration in STEAP1 expression, suggesting that STEAP1 protein is down-regulated by DHT. However, these results do not correlate with STEAP1 mRNA expression, suggesting that mechanisms at the translation level may be involved. In vitro results demonstrated that both STEAP1 mRNA and protein expression are down-regulated by DHT after 24h of stimulation.