STEAP1

Official Full Name

STEAP family member 1

Organism

Homo sapiens

GeneID

26872

Background

This gene is predominantly expressed in prostate tissue, and is found to be upregulated in multiple cancer cell lines. The gene product is predicted to be a six-transmembrane protein, and was shown to be a cell surface antigen significantly expressed at cell-cell junctions. [provided by RefSeq, Jul 2008]

Synonyms

STEAP; PRSS24;

Bio Chemical Class

Metal ion oxidoreductase

Protein Sequence

MESRKDITNQEELWKMKPRRNLEEDDYLHKDTGETSMLKRPVLLHLHQTAHADEFDCPSELQHTQELFPQWHLPIKIAAIIASLTFLYTLLREVIHPLATSHQQYFYKIPILVINKVLPMVSITLLALVYLPGVIAAIVQLHNGTKYKKFPHWLDKWMLTRKQFGLLSFFFAVLHAIYSLSYPMRRSYRYKLLNWAYQQVQQNKEDAWIEHDVWRMEIYVSLGIVGLAILALLAVTSIPSVSDSLTWREFHYIQSKLGIVSLLLGTIHALIFAWNKWIDIKQFVWYTPPTFMIAVFLPIVVLIFKSILFLPCLRKKILKIRHGWEDVTKINKTEICSQL

Open

Disease

Prostate cancer

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

STEAP1 (Six-Transmembrane Epithelial Antigen of the Prostate 1) is located on human chromosome 7q21.2, encoding a six-transmembrane protein that belongs to the STEAP family (including STEAP1-4). Its protein structure includes an N-terminal ferric reductase domain, a transmembrane region, and a C-terminal cytoplasmic domain, exhibiting metal ion transport and redox enzyme activity. This gene is primarily localized to the plasma membrane, especially enriched at cell junctions, and its expression is regulated by the androgen receptor (AR) signaling pathway. It is highly expressed at the basal level in prostate tissues and is also present in other tissues, including the bladder and ovaries. The core molecular function of STEAP1 is its ferric reductase activity: by reducing trivalent iron (Fe³⁺) to divalent iron (Fe²⁺), it promotes cellular iron uptake, thereby participating in energy metabolism and maintaining redox balance. Additionally, STEAP1 activates PI3K/AKT signaling pathways to regulate cell proliferation, differentiation, and migration processes.

Figure 1. Model of STEAP1-mediated gene regulation in colorectal and hepatocellular carcinoma. (Nakamura H, et al., 2023)

Biological Function and Pathological Mechanisms

STEAP1 plays a key role in maintaining cellular iron homeostasis. Iron, as a cofactor for mitochondrial respiratory chain complexes, when metabolized abnormally, directly leads to the accumulation of reactive oxygen species (ROS) and DNA damage. In malignant tumors, STEAP1 overexpression drives tumor progression through a dual mechanism: on the one hand, enhanced iron uptake supports the energy requirements of rapidly proliferating cancer cells; on the other hand, the activated PI3K/AKT pathway inhibits apoptosis and promotes epithelial-mesenchymal transition (EMT), thereby enhancing invasiveness.

Studies have shown that STEAP1 expression is increased 5–10 times in prostate cancer compared to normal tissues and is associated with the progression of castration-resistant prostate cancer (CRPC). In Ewing's sarcoma and ovarian cancer, overexpression of STEAP1 is also positively correlated with metastatic risk, potentially by regulating the activity of metalloproteinases (MMPs) to disrupt the extracellular matrix. Notably, mutations in STEAP1 can lead to iron metabolism disorders. For example, in prostatic intraepithelial neoplasia (PIN), the loss of STEAP1 function causes oxidative stress accumulation, accelerating the transition from precancerous lesions to invasive cancer.

Clinical Translation Research Progress

Based on the specific high expression of STEAP1 on tumor cell surfaces, it has become a promising target for antibody-drug conjugates (ADC) and Chimeric Antigen Receptor T-cell (CAR-T) therapies:

Antibody-Drug Conjugates: AMG 509 is a bispecific T-cell engager targeting STEAP1, and its Phase I clinical trial (NCT04221542) demonstrated an objective response rate (ORR) of 36% in metastatic CRPC patients, with good tolerability. This drug works by binding STEAP1 and the CD3 receptor, thereby recruiting T-cells to kill tumors.
CAR-T Therapy: The CAR-T construct developed by Amgen, targeting STEAP1, includes an anti-STEAP1 single-chain antibody (scFv), a 4-1BB co-stimulatory domain, and a CD3ζ activation domain. Preclinical studies have shown that it can eliminate 90% of tumor load in a prostate cancer xenograft model. Currently, this therapy is in Phase I/II clinical trials (NCT04824794), with preliminary data showing manageable cytokine release syndrome (CRS) risk in patients with recurrent/refractory solid tumors.

Moreover, STEAP1 immunohistochemical detection has been incorporated into prostate cancer diagnostic guidelines (e.g., NCCN), and its expression levels can serve as a biomarker to predict resistance to androgen deprivation therapy (ADT).

Challenges and Future Directions

Despite the promising outlook for STEAP1-targeted therapies, there are key challenges:

Off-target Toxicity: Physiological expression of STEAP1 in normal prostate basal cells and bladder epithelium could cause treatment-related damage. Preclinical models have shown that AMG 509 can lead to transient urinary obstruction, indicating the need for optimized dosing schedules or the development of tissue-specific delivery systems.
Resistance Mechanisms: Iron overload in the tumor microenvironment may exacerbate oxidative damage through the Fenton reaction, prompting cancer cells to upregulate antioxidant genes (such as NRF2) and weakening therapeutic responses. The combination with iron chelators (e.g., Deferasirox) could reverse resistance.

Future research should focus on multi-omics-guided personalized treatment strategies. For example, screening for iron metabolism abnormalities based on KEAP1/NRF2 pathway gene variants (e.g., rs1048290) could enhance the precision of STEAP1 inhibitors. Additionally, exploring the co-expression patterns of STEAP1 and immune checkpoints (e.g., PD-L1) will provide a theoretical basis for combination immunotherapy.

Reference

Nakamura H, Arihara Y, Takada K. Targeting STEAP1 as an anticancer strategy. Front Oncol. 2023 Oct 16;13:1285661.

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