Steroid Hormones, Hormone Secretion, and Steroid Receptors in Carcinogenesis
Velibor Krsmanović, James F. Whitfield in Malignant Cell Secretion, 2019
The structure of the androgen receptor (AR) is very similar to that of other steroid receptors. Androgen-sensitive cells contain receptor proteins capable of binding testosterone, 5 a-dihydrotestosterone, or the synthetic androgen. The molybdate stabilized cytosolic androgen receptor has an 8- to 9-S value. It contains the 90-kDa heat-shock protein which dissociates from the receptor upon activation.82 There are two isoforms of the inactive androgen receptor, but the structure of these isoforms are unknown. The association of a small acidic molecule or a cytosolic RNA with the androgen receptor may be responsible for this heterogeneity of the inactive receptors.82,83 The activation of the androgen receptor is accompanied by its conversion into 4.1- to 4.5-S subunits and the release of the 90-kDa heat-shock protein. Once activated, the 4.5-S androgen receptor further converts to a 7.0S form which moves to target cell nuclei. The converted form of androgen receptor from the rat prostate, rat submandibular gland, and thymus, as well as that from the mouse submandibular gland, consists of a steroid-binding subunit and RNA.84 However, there is no evidence that RNA is part of the androgen receptor. Interaction of RNA with glucocorticoid and estrogen receptors has also been reported,84,85 but we do not know whether this association of RNA with steroid receptors has any physiological significance.
Endocrine Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The action of DHT in a tumor cell is shown in Figure 8.20. Once DHT has been produced within the cell, it binds to the Androgen Receptor (AR) (Figure 8.20B) which is a monomeric protein of molecular weight 120 kDa, resulting from genes on the X chromosome (Figure 8.20A). There are two isoforms (AR-A and AR-B) of the human AR, and the structural domains of the two isoforms include a Ligand-Binding Domain (LBD) and a DNA-Binding Domain (DBD). A. Structural domains of the two isoforms (AR-A and AR-B) of the human Androgen Receptor (AR). The numbers above the bars refer to the amino acid residues that separate the domains, starting from the left-hand N-terminus to the right-hand C-terminus (NTD = N-Terminal Domain, DBD = DNA-Binding Domain, LBD = Ligand-Binding Domain, AF = Activation Function); B. Model of the ligand-binding domain (LBD) of the AR showing testosterone (white) complexed within the protein (red circle) causing a conformational change. Dihydrotestosterone (DHT) binds in a similar manner but with a higher affinity.
TCM safety and regulations
Raymond Cooper, Chun-Tao Che, Daniel Kam-Wah Mok, Charmaine Wing-Yee Tsang in Chinese and Botanical Medicines, 2017
PSA is a glycoprotein enzyme which is needed for the ejaculation of sperm in males. It is also detected in serum of healthy individuals; however, higher serum levels are detected in individuals with prostate cancer or other prostate disorders. Prostate cancer cells may have androgen receptors for its survival. Hormone therapy is usually used to treat these androgen-dependent (AD) prostate cancers. However, the AD prostate cancer may become resistant to the hormone therapy (androgen independent, AI) and resume growth after a few years of treatment. The treatment options for AI prostate cancer are scarce. Several reports suggested that PC-SPES might be helpful to treat AI prostate cancer. However, in the follow-up clinical studies, some of the patients receiving PC-SPES began to experience breast enlargement and tenderness, and loss of libido, responses usually associated with an estrogen treatment. An analysis of the PC-SPES in 1998 suggested that the active ingredients are distinct from some well-known estrogens including diethylstilbestrol, estrone, and estradiol. This stimulated further studies to isolate and identify the active compounds and some researchers at first considered that the compounds such as baicalin or licochalcone A were responsible for the biological activity.
Rewiring of miRNA-mRNA bipartite co-expression network as a novel way to understand the prostate cancer related players
Published in Systems Biology in Reproductive Medicine, 2023
Mohammad Mehdi Naghizadeh, Behnaz Bakhshandeh, Farshid Noorbakhsh, Marjan Yaghmaie, Ali Masoudi-Nejad
β-catenin is a core component of the complex of proteins that constitutes adherens junctions, which is essential for the stabilization and activation of the Wnt/β-catenin signaling pathway (Bakhshandeh et al. 2012; Pai et al. 2017). Perturbation in this pathway may involve various tumors or neoplasm like colorectal (Cheng et al. 2019), breast (Krishnamurthy and Kurzrock 2018), ovarian (Arend et al. 2013), bladder (Zhou et al. 2019), and prostate cancer as well (Murillo-Garzon and Kypta 2017). Schneider JA and Logan SK previously discussed the crosstalk between Wnt/β-catenin signaling and androgen receptors which highlights the role of β-catenin (Schneider and Logan 2018). Androgen receptor regulates gene expressions with diverse functions located downstream of the androgen response element, including secreted proteins, growth stimulators, transcription factors, and cell cycle regulators (Fujita and Nonomura 2019). Epithelial androgen receptor, in normal prostate, acts to supply secretory proteins to the prostate gland, such as prostate-specific antigen and stromal androgen receptor plays a role in prostate growth (Fujita and Nonomura 2019).
Safety of testosterone therapy in men with prostate cancer
Published in Expert Opinion on Drug Safety, 2019
Abraham Morgentaler, Monica Caliber
The Androgen receptor (AR) is present in many tissues, including normal and malignant prostate tissue, and mediates the effect of androgens. Free testosterone enters the cell, is reduced by 5-alpha reductase to dihydrotestosterone (DHT), which has a higher affinity for the AR compared with testosterone. The weaker androgenic potency of testosterone compared to that of dihydrotestosterone resides in its weaker interaction with the androgen receptor [73]. The complex of androgen-AR then transposes to the cell nucleus where it binds to androgen response elements on DNA and stimulates production of androgen-dependent gene products. Interestingly, finasteride blocks reduction of testosterone to DHT, causing reduction in prostate volume. In the large Prostate Cancer Prevention Trial, finasteride reduced the number of diagnosed PCa compared to placebo but did not alter the number of high-grade PCa cases [74].
Current androgen receptor antagonists under investigation for resistant prostate cancer
Published in Expert Review of Anticancer Therapy, 2022
Maria Concetta Nigro, Veronica Mollica, Andrea Marchetti, Michael Cheng, Matteo Rosellini, Rodolfo Montironi, Liang Cheng, Francesco Massari
Prostate cancer (PCa) is one of the most frequent neoplasms in males and represents the second most common cause of cancer-related deaths in men [1]. In the localized disease, the standard of care treatment consists of a radical approach based on prostatectomy, radiation therapy, or brachytherapy [2–5]. Androgen receptor signaling plays a pivotal role in the development and progression of prostate cancer, especially in the evolution to an advanced stage [6]. In fact, testosterone and 5α-dihydrotestosterone are involved not only in the physiological growth and function of normal prostate gland, but also in the development of prostate tumor, through multiple mechanism including altered expression of androgen receptors (AR) and of AR co-activators and co-regulators that lead to the hyperactivation of androgen receptors signaling pathway.
Related Knowledge Centers
- Cytoplasm
- Dihydrotestosterone
- Nuclear Receptor
- Testosterone
- Cell Nucleus
- Androgen
- Hormone
- Progesterone Receptor
- Progestogen
- DNA-Binding Protein