Six Transmembrane Epithelial Antigen Of The Prostate 1 Expression Research Articles

Inhibition of STEAP1 ameliorates inflammation and ferroptosis of acute lung injury caused by sepsis in LPS-induced human pulmonary microvascular endothelial cells.

Ferroptosis plays an important part in Acute lung injury (ALI) caused by sepsis. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) has potential effects on iron metabolism and inflammation but reports on its function in ferroptosis and sepsis-caused ALI are lacking. Here we explored the role of STEAP1 in sepsis-caused ALI and the possible mechanisms. Lipopolysaccharide (LPS) was added to human pulmonary microvascular endothelial cells (HPMECs) to form the sepsis-caused ALI model in vitro. The Cecal ligation and puncture (CLP) experiment was performed on C57/B6J mice to form the sepsis-caused ALI model in vivo. The effect of STEAP1 on inflammation was investigated by PCR, ELISA, and Western blot for the inflammatory factors and adhesion molecular. The reactive oxygen species (ROS) levels were detected by immunofluorescence. The effect of STEAP1 on ferroptosis was investigated by detecting malondialdehyde (MDA) levels, glutathione (GSH) levels, Fe2+ levels, cell viability, and mitochondrial morphology. Our findings suggested that STEAP1 expression was increased in the sepsis-induced ALI models. Inhibition of STEAP1 decreased the inflammatory response and ROS production as well as MDA levels but increased the levels of Nrf2 and GSH. Meanwhile, inhibition of STEAP1 improved cell viability and restored mitochondrial morphology. Western Blot results showed that inhibition of STEAP1 could affect the SLC7A11/GPX4 axis. Inhibition of STEAP1 may be valuable for pulmonary endothelial protection in lung injury caused by sepsis.

STEAP1 Knockdown Decreases the Sensitivity of Prostate Cancer Cells to Paclitaxel, Docetaxel and Cabazitaxel.

The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) protein has been indicated as an overexpressed oncoprotein in prostate cancer (PCa), associated with tumor progression and aggressiveness. Taxane-based antineoplastic drugs such as paclitaxel, docetaxel, or cabazitaxel, have been investigated in PCa treatment, namely for the development of combined therapies with the improvement of therapeutic effectiveness. This study aimed to evaluate the expression of STEAP1 in response to taxane-based drugs and assess whether the sensitivity of PCa cells to treatment with paclitaxel, docetaxel, or cabazitaxel may change when the STEAP1 gene is silenced. Thus, wild-type and STEAP1 knockdown LNCaP and C4-2B cells were exposed to paclitaxel, docetaxel or cabazitaxel, and STEAP1 expression, cell viability, and survival pathways were evaluated. The results obtained showed that STEAP1 knockdown or taxane-based drugs treatment significantly reduced the viability and survival of PCa cells. Relatively to the expression of proliferation markers and apoptosis regulators, LNCaP cells showed a reduced proliferation, whereas apoptosis was increased. However, the effect of paclitaxel, docetaxel, or cabazitaxel treatment was reversed when combined with STEAP1 knockdown. Besides, these chemotherapeutic drugs may stimulate the cell growth of PCa cells knocked down for STEAP1. In conclusion, this study demonstrated that STEAP1 expression levels might influence the response of PCa cells to chemotherapeutics drugs, indicating that the use of paclitaxel, docetaxel, or cabazitaxel may lead to harmful effects in PCa cells with decreased expression of STEAP1.

STEAP1 regulation and its influence modulating the response of LNCaP prostate cancer cells to bicalutamide, enzalutamide and apalutamide.

Anti‑androgen drugs are the standard pharmacological therapies for treatment of non‑metastatic prostate cancer (PCa). However, the response of PCa cells may depend on the anti‑androgen used and often patients become resistant to treatment. Thus, studying how the anti‑androgen drugs affect oncogenes expression and action and the identification of the best strategy for combined therapies are essential to improve the efficacy of treatments. The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) is an oncogene associated with PCa progression and aggressiveness, although its relationship with the androgen receptor signaling remains to be elucidated. The present study aimed to evaluate the effect of anti‑androgens in regulating STEAP1 expression and investigate whether silencing STEAP1 can make PCa cells more sensitive to anti‑androgen drugs. For this purpose, wild‑type and STEAP1 knockdown LNCaP cells were exposed to bicalutamide, enzalutamide and apalutamide. Bicalutamide decreased the expression of STEAP1, but enzalutamide and apalutamide increased its expression. However, decreased cell proliferation and increased apoptosis was observed in response to all drugs. Overall, the cellular and molecular effects were similar between LNCaP wild‑type and LNCaP‑STEAP1 knockdown cells, except for c‑myc expression levels, where a cumulative effect between anti‑androgen treatment and STEAP1 knockdown was observed. The effect of STEAP1 knockdown alone or combined with anti‑androgens in c‑myc levels is required to be addressed in future studies.

The Prognostic Value and Immunological Role of STEAP1 in Pan-Cancer: A Result of Data-Based Analysis.

Purpose This study is aimed at systematically analyzing the expression, function, and prognostic value of six transmembrane epithelial antigen of the prostate 1 (STEAP1) in various cancers. Methods The expressions of STEAP1 between normal and tumor tissues were analyzed using TCGA and GTEx. Clinicopathologic data was collected from GEPIA and TCGA. Prognostic analysis was conducted by Cox proportional hazard regression and Kaplan-Meier survival. DNA methylation, mutation features, and molecular subtypes of cancers were also investigated. The top-100 coexpressed genes with STEAP1 were involved in functional enrichment analysis. ESTIMATE algorithm was used to analyze the correlation between STEAP1 and immunity value. The relationships of STEAP1 and biomarkers including tumor mutational burden (TMB), microsatellite instability (MSI), and stemness score as well as chemosensitivity were also illustrated. Results Among 33 cancers, STEAP1 was overexpressed in 19 cancers such as cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), colon adenocarcinoma, and lymphoid neoplasm diffuse large B cell lymphoma while was downregulated in 5 cancers such as adrenocortical carcinoma, breast invasive carcinoma (BRCA), and kidney chromophobe renal cell carcinoma. STEAP1 has significant prognostic relationships in multiple cancers. 15 cancers exhibited differences of DNA methylation including bladder urothelial carcinoma, BRCA, and CESC. STEAP1 expression was positively correlated to immune molecules especially in thyroid carcinoma and negatively especially in uveal melanoma. STEAP1 was associated with TMB and MSI in certain cancers. In addition, STEAP1 was connected with increased chemosensitivity of drugs such as trametinib and pimasertib. Conclusions STEAP1 was an underlying target for prognostic prediction in different cancer types and a potential biomarker of TMB, MSI, tumor microenvironment, and chemosensitivity.

Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing's Sarcoma.

Ewing’s sarcoma (ES) is caused by a chromosomal translocation leading to the formation of the fused EWSFLI1 gene, which codes for an aberrant transcription factor EWSFLI1. The transcriptional targets of EWSFLI1 have been viewed as promising and novel drug targets in the treatment of ES. One such target is six transmembrane epithelial antigen of the prostate 1 (STEAP1), a transmembrane protein that is upregulated by EWSFLI1 in ES. STEAP1 is a hallmark of tumor invasiveness and an indicator of tumor responsiveness to therapy. EWSFLI1 binds to the STEAP1 promoter region, but the mechanism of action by which it upregulates STEAP1 expression in ES is not entirely understood. Upon analysis of the STEAP1 promoter, we predicted two binding sites for NKX2.2, another crucial transcription factor involved in ES pathogenesis. We confirmed the interaction of NKX2.2 with the STEAP1 promoter using chromatin immunoprecipitation (ChIP) analysis. We used single-molecule RNA imaging, biochemical, and genetic studies to identify the novel role of NKX2.2 in regulating STEAP1 expression in ES. Our results show that NKX2.2 is a co-regulator of STEAP1 expression and functions by interacting with the STEAP1 promoter at sites proximal to the reported EWSFLI1 sites. The co-operative interaction of NKX2.2 with EWSFLI1 in regulating STEAP1 holds potential as a new target for therapeutic interventions for ES.

Abstract DDT02-03: AMG 509: A novel, humanized, half-Life extended, bispecific STEAP1 × CD3 T cell recruiting XmAb® 2+1 antibody

Abstract AMG509, a novel STEAP1 x CD3 T cell-recruiting XmAb® 2+1 bispecific immune therapy for the treatment of prostate cancer and Ewing sarcoma. Metastatic castration resistant prostate cancer (mCRPC) and Ewing sarcoma (EWS) are both diseases with unmet medical needs. Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) is a cell surface antigen that is induced by androgens and highly expressed in prostate cancer. STEAP1 is also highly expressed in EWS, and it is a target of the EWS/FLI1 fusion, the primary oncogenic driver in this pediatric malignancy. AMG 509 is a novel, half-life extended, cynomolgus monkey cross-reactive, STEAP1 x CD3 T cell-recruiting XmAb® 2+1 bispecific antibody designed to treat STEAP1-expressing cancers. AMG 509 contains two identical humanized anti-STEAP1 Fab domains that bind STEAP1-expressing cells, an anti-CD3 scFv domain that binds T cells, and an Fc domain engineered to lack effector function and extend serum half-life. We found that membranous STEAP1 expression, as measured by IHC, was absent from most normal tissues (FDA normal organ tissue array, n = 72) except the prostate epithelium and a subset of lung macrophages. In contrast, we found membranous STEAP1 expression by IHC in 80% of primary prostate cancer tumors (n = 80) and moderate to high expression in 83% of metastatic prostate cancer lesions (n = 181) and 77% of bone metastases (n = 31). In addition, we found STEAP1 expression by IHC in all EWS cell lines (n=13) and xenograft models tested (n=12). AMG 509 bound to recombinant human and cynomolgus monkey CD3ϵ with a KD of 27.6 nM and 25.8 nM, respectively, and to 293T cells transfected with human or cynomolgus monkey STEAP1 with an EC50 of 3.8 nM and 3.1 nM, respectively. AMG 509 triggered potent T cell-redirected lysis of STEAP1-positive cancer cells, with a median EC50 of 18.9 pM across 17 different STEAP1-expressing prostate, EWS, gastric, and melanoma cancer cell lines. AMG 509 was 50-fold more potent in inducing the redirected lysis of C4-2B prostate cancer cells in vitro than an XmAb® molecule with a single anti-STEAP1 Fab domain. AMG 509 was also specific, as it showed no activity against C4-2B cancer cells engineered to lack STEAP1 expression. AMG 509 exhibited hallmarks of T-cell engagement in vitro, including T-cell proliferation and cytokine release. It also induced robust in vivo anti-tumor activity in prostate cancer and EWS xenograft models, with concomitant CD8+ T-cell activation and expansion in tumors. Data from a nonclinical safety study conducted in the cynomolgus monkey suggest that AMG 509 can be administered safely at doses that are predicted to be clinically active. AMG 509 is a potent and specific first-in-class T cell-recruiting antibody for the treatment of STEAP1-positive malignancies. We are currently evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG 509 in a phase 1, first-in-human study in patients with mCRPC (NCT04221542). Citation Format: Olivier Nolan-Stevaux. AMG 509: A novel, humanized, half-Life extended, bispecific STEAP1 × CD3 T cell recruiting XmAb® 2+1 antibody [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr DDT02-03.

Six-transmembrane epithelial antigen of the prostate 1 expression promotes ovarian cancer metastasis by aiding progression of epithelial-to-mesenchymal transition.

Ovarian cancer is a severe malignant tumour of the female genital organs. Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) expression is correlated with the occurrence and progression of multiple cancers. Here, we assessed STEAP1 expression in ovarian cancer and explored the relationship between STEAP1 and ovarian cancer progression. We used immunohistochemistry and public databases to test STEAP1 expression in normal human ovarian tissues, benign ovarian tumours, and ovarian cancer. The expression of STEAP1 and epithelial-to-mesenchymal transition (EMT)-related genes was analysed using immunocytochemistry, quantitative reverse transcription polymerase chain reaction, and western blotting in ovarian cancer cell lines. Lentivirus was used to knockdown and overexpress STEAP1. Invasion, migration, growth, clonogenicity, and apoptosis were assessed using transwell assay, growth curve, plate clone formation assay, and flow cytometry. We used a tumour xenograft to verify the relationship between STEAP1 and in vivo ovarian cancer cell growth. Matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) activities were examined using Matrix metalloproteinase zymography assay. STEAP1 was highly expressed in the human ovarian cancer tissues and a highly invasive ovarian cancer cell line. Overexpression of STEAP1 was related to poor prognosis in ovarian cancer patients. Down-regulation of STEAP1 suppressed the invasion, migration, proliferation, clonogenicity, EMT progression in human ovarian cancer cells and xenograft tumour growth in vivo, but it enhanced apoptosis. In human ovarian cancer, the STEAP1 gene is highly expressed, and its function is correlated with human ovarian cancer cell metastasis and growth. STEAP1 may be a possible target for suppressing ovarian cancer metastasis.

Six-transmembrane epithelial antigen of the prostate 1 is associated with tumor invasion and migration in endometrial carcinomas.

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1), a member of the STEAP family, is a general tumor antigen. However, no information has been available to date regarding the function of STEAP1 in the progression of endometrial carcinoma. In this study, we used in vitro and in vivo strategies to prove that STEAP1 plays an important role in the progression of endometrial carcinoma. Immunohistochemistry, immunocytochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and Western blot analysis were used to detect the expression of STEAP1 in normal endometrial cells and endometrial cancer cell lines. The progression of the cell cycle, plate clone formation assay, and transwell migration and invasion assays were performed to examine the effects of STEAP1 on cell proliferation, clonogenicity, migration, and their invasive capacity. In addition, we confirmed that STEAP1 was tightly correlated with the development of tumor in vivo. The relationship between epithelial to mesenchymal transition (EMT) and STEAP1 expression was evaluated by RT-qPCR and Western blot analysis. Matrix metalloproteinase (MMP) zymography assay was used to detect the activities of MMP2 and MMP9. STEAP1 was restrictively expressed in endometrial carcinoma and downregulation of the STEAP1 gene increased proliferation and clonogenicity, as well as promoted cell migration, invasion, and the progress of EMT. STEAP1 is downregulated in endometrial carcinoma and can restrict migration and invasion of endometrial carcinoma cells. Overall, STEAP1 may be an ideal target for tumor therapy and diagnosis in the future.

Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer.

The over-expression of six-transmembrane epithelial antigen of the prostate 1 (STEAP1) underlies the pathogenesis of a large subset of human cancers. Expressed on the cancer cell surface, STEAP1 is an attractive target for antibody-based therapy or immunotherapy. However, its role in modulating the pathophysiology of colorectal cancer (CRC) remains relatively unexplored. In this study, we first demonstrated that the STEAP1 transcript level was significantly higher in CRC tissues than in normal colonic tissues. Of note, STEAP1 expression negatively correlated with overall survival as determined from a publicly accessible gene expression profile data set. A loss-of-function approach in cultured CRC cell lines revealed that STEAP1 silencing suppressed cell growth and increased reactive oxygen species (ROS) production, followed by apoptosis, through an intrinsic pathway. Mechanistically, the inhibition of STEAP1 was associated with decreased expression of antioxidant molecules regulated by the transcription factor, nuclear erythroid 2-related factor (NRF2), in CRC cells. Taken together, we identified high STEAP1 transcript levels leading to reduced ROS production that prevented apoptosis via the NRF2 pathway in CRC cells as a pathological mechanism in CRC. This study highlights the STEAP1-NRF2 axis as a therapeutic target for CRC and its manipulation as a novel strategy to conquer CRC.

The Prognostic Role of STEAP1 Expression Determined via Immunohistochemistry Staining in Predicting Prognosis of Primary Colorectal Cancer: A Survival Analysis.

STEAP1 (six transmembrane epithelial antigen of the prostate 1) is a transmembrane protein that functions as a potential channel or transporter protein. It is overexpressed in certain cancers and is viewed as a promising therapeutic target. However, the prognostic role of STEAP1 is still controversial, and no role for STEAP1 has yet been indicated in colorectal cancer. The aim of this study was to investigate the possible association of STEAP1 expression with colorectal cancer prognosis. STEAP1 expression was analyzed by immunohistochemical staining of a tissue array of 165 cancer specimens from primary colorectal cancer patients. The mean and medium follow-up times after surgery were 5.1 and 3.9 years, respectively. A total of 139 patients died during the 13 years of follow-up in the survey period. The prognostic value of STEAP1 with respect to overall survival was analyzed by Kaplan-Meier analysis and Cox proportional hazard models. In total, 164 samples displayed detectable STEAP1 expression in the cytoplasm and membrane. Low STEAP1 expression was correlated with poor overall survival (five-year survival: 33.7% vs. 57.0%, low expression vs. high expression, p = 0.020). Accordingly, multivariate analysis identified low STEAP1 expression as an independent risk factor (hazard ratio = 1.500, p = 0.018), especially in elderly patients or those with late stage cancers, late T values, and early N values. We suggest that analysis of STEAP1 expression by immunohistochemical staining could serve as an independent prognostic marker for colorectal patients. This finding should be validated by other investigative groups.

Six-transmembrane epithelial antigen of the prostate-1 plays a role for in vivo tumor growth via intercellular communication

Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a novel cell surface protein overexpressed only in the prostate among normal tissues and various types of cancer including prostate, bladder, lung, and ovarian cancer. Although its function in prostate and tumor cells has been remained unclear, due to its unique and restricted expression, STEAP-1 is expected to be an attractive target for cancer therapy. Here, we show that knockdown of STEAP-1 in human cancer cells caused the retardation of tumor growth compared with wild type in vivo. In contrast, STEAP-1 introduced tumor cells augmented the tumor growth compared with STEAP-1-negative wild type cells. Using dye transfer assay, we demonstrate that the STEAP-1 is involved in intercellular communication between tumor cells and adjacent tumor stromal cells and therefore may play a key role for the tumor growth in vivo. These data indicate the inhibition of the STEAP-1 function or expression can be a new strategy for cancer therapy.

A phase I study of the safety and pharmacokinetics of DSTP3086S, an anti-STEAP1 antibody-drug conjugate (ADC), in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).

5020 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (<5) after a single dose of DSTP3086S. CTC conversions were also observed at lower doses. PSA decreases of ≥ 50% were observed in 1 pt at 2.25 mg/kg, and 2 pts at 2.8 mg/kg who also had PCWG2 radiologic responses. Conclusions: DSTP3086S at the RP2D of 2.8 mg/kg q3w has a tolerable safety profile and shows evidence of anti-tumor activity. Enrollment in the expansion cohort is ongoing.

Six transmembrane epithelial antigen of the prostate 1 is down‐regulated by sex hormones in prostate cells

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. 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. 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. STEAP1 is down-regulated by DHT and E2 in LNCaP cells and in rat prostate.

High STEAP1 expression is associated with improved outcome of Ewing's sarcoma patients

Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimens.

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

Ewing tumors comprise the second most common type of bone-associated cancer in children and are characterized by oncogenic EWS/FLI1 fusion proteins and early metastasis. Compelling evidence suggests that elevated levels of intracellular oxidative stress contribute to enhanced aggressiveness of numerous cancers, possibly including Ewing tumors. Using comprehensive microarray analyses and RNA interference, we identified the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound mesenchymal stem cell marker of unknown function-as a highly expressed protein in Ewing tumors compared with benign tissues and show its regulation by EWS/FLI1. In addition, we show that STEAP1 knockdown reduces Ewing tumor proliferation, anchorage-independent colony formation as well as invasion in vitro and decreases growth and metastasis of Ewing tumor xenografts in vivo. Moreover, transcriptome and proteome analyses as well as functional studies revealed that STEAP1 expression correlates with oxidative stress responses and elevated levels of reactive oxygen species that in turn are able to regulate redox-sensitive and proinvasive genes. In synopsis, our data suggest that STEAP1 is associated with the invasive behavior and oxidative stress phenotype of Ewing tumors and point to a hitherto unanticipated oncogenic function of STEAP1.

STEAP1 expression in prostate cancer and its regulation by androgens

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.