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AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies
Mengnan Li1, Limin Zhang2,3, Jiahui Yu1
1School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China.
Abstract:
Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17β-estradiol (a potent estrogen), and 11β-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Novel AKR1C3 inhibitors, including natural products and analogues of existing drugs designed based on their structures and frameworks, continue to be discovered and developed in laboratories worldwide. The AKR1C3 enzyme has emerged as a key player in carcinoma progression and therapeutic resistance, posing challenges in cancer treatment. This review aims to provide a comprehensive analysis of AKR1C3's role in carcinoma development, its implications in therapeutic resistance, and recent advancements in the development of AKR1C3 inhibitors for tumor therapies.
Insights
Aldo-Keto Reductase Family 1 Member C3 (AKR1C3) drives cancer growth and treatment resistance by boosting androgen signaling. Inhibiting AKR1C3 shows promise for suppressing tumor progression and overcoming resistance in cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as 17β-HSD5, is crucial for androgen biosynthesis.
- Elevated AKR1C3 levels activate androgen receptor signaling, promoting tumor progression and therapeutic resistance.
- AKR1C3 overexpression is linked to poor prognosis and survival in carcinoma patients.
Purpose of the Study:
- To comprehensively review AKR1C3's role in carcinoma development.
- To analyze AKR1C3's implications in therapeutic resistance.
- To highlight recent advancements in AKR1C3 inhibitor development for cancer treatment.
Main Methods:
- Literature review of studies on AKR1C3 function, overexpression, and inhibition.
- Analysis of AKR1C3's enzymatic activity and its impact on steroid hormone metabolism.
- Examination of preclinical and clinical data on AKR1C3 inhibitors.
Main Results:
- AKR1C3 catalyzes the conversion of androgens and estrogens, influencing hormone-dependent cancers.
- AKR1C3 overexpression promotes cancer cell proliferation, invasion, and metastasis.
- Inhibition of AKR1C3 demonstrates significant efficacy in suppressing tumor growth and overcoming resistance.
Conclusions:
- AKR1C3 is a key oncogenic factor and a promising therapeutic target in carcinoma.
- Development of novel AKR1C3 inhibitors, including natural products, is advancing rapidly.
- Targeting AKR1C3 offers a potential strategy to improve cancer treatment outcomes.
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