Molecular Mechanisms Of Androgen Action Research Articles

Insights into Androgen Receptor Action in Lung Cancer

Sex hormones and their receptors play a crucial role in human sexual dimorphism and have been traditionally associated with hormone-dependent cancers like breast, prostate, and endometrial cancer. However, recent research has broadened our understanding by revealing connections with other types of cancers, such as lung cancer, where the androgen receptor has been found to be particularly significant. This review aims to explore the molecular mechanisms of androgen action in lung cancer pathogenesis and progression, highlighting the potential of inhibiting the androgen receptor signaling pathway as a therapeutic strategy for lung cancer treatment.

Comparative Study of Some Potential Paracrine Factors Produced by Normal and Androgenetic Alopecia Hair Follicles

Androgens are the main regulators of human hair growth. Paradoxically, androgens can convert small vellus hair follicles to long terminal ones as seen during growth of beard and in hirsutism, however they also can stimulate the gradual transformation of large terminal scalp follicles to tiny vellus ones causing androgenetic alopecia in individuals with a genetic predisposition. Hair disorders are poorly controlled and may cause psychological distress and reduction in the quality of life. The molecular mechanisms of androgen action in human hair follicles are not fully understood. However it is believed that androgens exert their effects on hair follicles via the dermal papilla cells by altering the regulatory paracrine factors produced by the dermal papilla itself and affect the other follicular components. The study aimed to identify key paracrine factors which involved in androgen-regulated alopecia. Balding and non-balding scalp hair follicles isolated and analyzed by molecular biological methods, DNA microarray and quantitative real-time PCR. Comparing balding and non-balding follicles from the same individuals revealed the expected reduction in several keratin and keratin-related protein genes supporting this approach’s validity. There were also significant differences in paracrine factors previously implicated in androgen action by in vitro studies. Several factors believed to increase during androgen stimulation of larger, darker follicles, e.g. IGF-I and SCF, and VEGV were lowered in balding follicles, while putative inhibitory factors, e.g. TGFs-1, IL-1β, IL-1α, and IL-6 were increased. These findings increase our understanding of androgen action in human hair follicles; this could lead to better treatments for hair disorders.

The Paradox Dividing Testosterone Deficiency Symptoms and Androgen Assays: A Closer Look at the Cellular and Molecular Mechanisms of Androgen Action

Central to the diagnosis and treatment of testosterone deficiency syndrome in the adult male is the remarkable paradox that there is a very poor correlation between the characteristic symptoms and levels of serum androgens. Because androgen deficiency can be associated with severe symptomatology, as well as diverse conditions such as coronary heart disease, diabetes, and metabolic syndrome, the aim was to present an evidence-based working hypothesis to resolve this confusing clinical paradox. A review of the possible mechanisms in testosterone deficiency syndrome was carried out, and a hypothesis to explain this paradox and associated problems in the diagnosis and clinical management of androgen deficiency was established on the basis of a review of the literature. The mechanisms by which androgen deficiency could arise were studied at five different levels: 1. Impaired androgen synthesis or regulation. 2. Increased androgen binding. 3. Reduced tissue responsiveness. 4. Decreased androgen receptor activity. 5. Impaired transcription and translation. As with insulin in maturity onset diabetes mellitus, there can be both insufficient production and variable degrees of resistance to the action of androgens operating at several levels in the body simultaneously, with these factors becoming progressively worse with aging, adverse lifestyle, other disease processes, and a wide range of medications. Using this model, androgen deficiency can be redefined as an absolute or relative deficiency of androgens or their metabolites according to the needs of that individual at that time in his life. There are important ways in which the considerations raised by this hypothesis affect the etiology, terminology, diagnosis, and treatment of androgen-deficient states.

Developmental aspects of androgen action

The formation of a testis from the indifferent gonad is the prelude to sequential steps in male sex differentiation orchestrated by time-dependent androgen biosynthesis and action. Information about the cellular and molecular mechanisms of androgen action can be obtained by the study of disorders of sex differentiation in males. The pivotal role of the androgen receptor as a ligand-induced transcription factor is emphasised and preliminary studies are described which attempt to identify developmentally regulated androgen-responsive genes. That androgen action can be modulated by gene polymorphisms is illustrated by the influence of an androgen receptor polyglutamine repeat in the multi-factorial causation of less severe forms of male undermasculinisation.

Cloning of the hamster androgen receptor gene

Flank organs of male Golden Syrian hamsters contain sebaceous glands and hair follicles whose morphology and function are highly dependent on androgen, which makes these organs a useful model to study androgen action. In order to investigate molecular mechanisms of androgen action, we cloned a cDNA encoding the hamster androgen receptor (hamAR) by polymerase chain reaction (PCR) amplification of hamster testis cDNA. Nucleotide sequence analysis revealed that the cDNA has the capacity to encode a polypeptide of 900 amino acid. The deduced amino acid sequence was highly homologous to those of androgen receptors (AR) from other species. Western blot analysis of COS1 cells transfected with a vector expressing hamAR revealed that the recombinant ham AR was identical in size to that of endogeneous ham AR expressed in liver, sebaceous glands and testis. We further demonstrated that transfection of the hamAR expression vector into COS1 cells resulted in activation of a luciferase reporter gene containing multiple androgen responsive elements (ARE) in a testosterone-dependent manner. Availability of the recombinant hamAR clone along with the flank organ system should provide a more powerful tool than currently available to investigate androgen action at the molecular level.

A cell culture model for androgen effects in motor neurons.

Androgens are known to alter the morphology, survival, and axonal regeneration of lower motor neurons in vivo. To understand better the molecular mechanisms of androgen action in neurons, we created a model system by stably expressing the human androgen receptor (AR) in motor neuron hybrid cells. Motor neuron hybrid cells express markers consistent with anterior horn cells and can be differentiated into a neuronal phenotype. When differentiated in the presence of androgen, AR-expressing cells, but not control cells, exhibit a dose-dependent change in morphology: androgen-treated cells develop larger cell bodies and broader neuritic processes while continuing to express neuronal markers. In addition, androgen promotes the survival of AR-expressing cells, but not control cells, under low-serum conditions. Our results demonstrate a direct trophic effect of androgens on lower motor neurons, mediated through the AR expressed in this population of neurons.

Androgen-regulated proliferation and gene transcription in a prostate smooth muscle cell line (PS-1)

Androgens play a key role in directing stromal-epithelial interactions in prostate gland development, in maintenance of adult phenotype, and in disease progression. To address the molecular mechanisms of androgen action in prostate stromal cells and the genes regulated by androgens in this cell type, a stromal cell line (PS-1) was developed from rat ventral prostate. The PS-1 cell line was adapted to chemically defined media and characterized as smooth muscle based on expression of desmin, smooth muscle alpha-actin, and nuclear androgen receptor, markers for prostate smooth muscle. To examine steroid hormone regulation, PS-1 cells were analyzed for response to a panel of steroid hormones in serum-free, chemically defined media. PS-1 cells were significantly growth stimulated by physiological concentrations of androgens (10nM) relative to other steroids tested. To ascertain whether this cell line could be used to examine androgen-regulated gene expression, differential display PCR was used to demonstrate the presence of androgen-regulated transcripts and provide the initial steps in cloning these genes. Replicate differential display PCR analyses showed consistent androgen stimulation of 16 messenger RNA species. Northern analysis confirmed androgen regulation of 6 species. Sequence analysis of each indicated no regions of significant homology or direct matches to existing sequences. Further study of the PS-1 stromal cell line and androgen-regulated genes identified here will provide a novel in vitro system for defining molecular mechanisms of androgen action in prostate stromal cells and the significance of stromal androgen-regulated genes to stromal-epithelial interactions.

Androgen-regulated proliferation and gene transcription in a prostate smooth muscle cell line (PS-1).

Androgens play a key role in directing stromal-epithelial interactions in prostate gland development, in maintenance of adult phenotype, and in disease progression. To address the molecular mechanisms of androgen action in prostate stromal cells and the genes regulated by androgens in this cell type, a stromal cell line (PS-1) was developed from rat ventral prostate. The PS-1 cell line was adapted to chemically defined media and characterized as smooth muscle based on expression of desmin, smooth muscle alpha-actin, and nuclear androgen receptor, markers for prostate smooth muscle. To examine steroid hormone regulation, PS-1 cells were analyzed for response to a panel of steroid hormones in serum-free, chemically defined media. PS-1 cells were significantly growth stimulated by physiological concentrations of androgens (10nM) relative to other steroids tested. To ascertain whether this cell line could be used to examine androgen-regulated gene expression, differential display PCR was used to demonstrate the presence of androgen-regulated transcripts and provide the initial steps in cloning these genes. Replicate differential display PCR analyses showed consistent androgen stimulation of 16 messenger RNA species. Northern analysis confirmed androgen regulation of 6 species. Sequence analysis of each indicated no regions of significant homology or direct matches to existing sequences. Further study of the PS-1 stromal cell line and androgen-regulated genes identified here will provide a novel in vitro system for defining molecular mechanisms of androgen action in prostate stromal cells and the significance of stromal androgen-regulated genes to stromal-epithelial interactions.

Characterization of human androgen receptor overexpressed in the baculovirus system.

An essential step in the process of understanding the structure and function of the human androgen receptor (hAR) involves the production of large quantities of the hAR. For this purpose, the full-length hAR has been overproduced in insect cells by using a baculovirus genetic expression system. The recombinant hAR is produced in Sf21 insect cells at approximately 7 pmol/mg of protein (1 x 10(6) AR molecules per cell), which is 70-150 times greater than levels detected in androgen target tissues. Androgen can bind to the baculovirus-expressed hAR with high affinity (Kd = 0.46 nM), and the specificity of hormone binding in baculovirus-expressed hAR is essentially identical to that of bona fide hAR. An anti-AR monoclonal antibody can recognize the baculovirus-expressed hAR at approximately 100 kDa upon Western blot analysis. Sucrose gradient analysis shows that baculovirus-expressed hAR complexes sediment at 4 S in a high salt medium and these complexes can interact with anti-AR monoclonal antibody to form complexes that sediment at 8-10 S. Therefore, production of recombinant hAR from the baculovirus expression system will provide an alternative source of biologically active hAR for studies on the molecular mechanisms of androgen action.

Chick-comb fibroblasts a new strain of cultured cells sensitive to androgens

An androgen-responsive cell strain of chick-comb fibroblasts has been established in culture. Cells were obtained from combs of 1–2 day old white Leghorn cockerels and cultured in Dulbecco's modified Eagle medium supplemented with 10% fetal calf serum and 6 g/1 glucose. The cells required serum but not androgens for growth. In the presence of androgens, growth rate and incorporation of labeled precursors into protein and RNA were markedly increased in exponentially growing cells, but not in confluent cultures. Androgens exerted these stimulatory effects in a dose-dependent fashion. It is concluded that chick-comb fibroblasts, which respond to androgens in vivo, retain this responsiveness when cultured. They furnish a well-defined system of potential value for studies of the molecular mechanisms of androgen action.