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    • Intracellular Signaling Cascades From ligand sensitization

    2024-03-20

    Intracellular Signaling Cascades. From ligand sensitization to translation of genes, all cellular processes are dependent on the intracellular levels and activity of partners involved in the signaling pathway. These signaling events lead to critical post-translational modifications including phosphorylation, sumoylation, ubiquitination and others that are important for the function of the receptor. The intracellular levels of kinases and phosphatases and the availability of growth factors promote the genomic, non-genomic, and ligand-independent activation of the AR. Similar to the coactivators, distinct signaling cascades regulate the function of transcription factors. These are due to multiple players acting in an orchestrated fashion to mediate their effects. Testosterone signals through inhibition of p38 MAPK, Notch-1, Notch-2 and Jagged-1 signaling pathways in macrophages, but Firefly Luciferase utilize PI3K-Akt pathway in bone Firefly Luciferase (Guo et al., 2004, Kang et al., 2004, Liu et al., 2006). This suggests that each ligand uniquely influences distinct pathways depending on cell and tissue type to mediate its pharmacologic and physiological response (Huber et al., 2001). AR phosphorylation is also affected ligand-dependently and -independently through growth factor alterations leading to divergent physiological responses (Dehm and Tindall, 2006). Literature evidence suggests that non-genomic effects are also important for the anabolic effects of androgens and estrogens (Kousteni et al., 2001), whereas nuclear genomic effects are critical for the development of sexual organs. In addition to the nuclear AR, AR is also thought to be located at the plasma membrane to mediate rapid non-genomic effects. For example, the progression of meiosis that requires ERK occurs without the requirement for transcription. The ability of a ligand to promote non-genomic activation in cells will also determine its cell-type-specific function (Lutz et al., 2003, Lutz et al., 2001, Lutz et al., 2000). We demonstrated that the SARMs and DHT utilize distinct signaling pathways to promote their genomic and non-genomic effects. An arylproprionamide SARM mediated its actions through Src kinase, MEK-1/2 or MEK-3, ERK and p38 MAPK pathways, while DHT primarily affected the IP3, PLC, PI3K, PKC, ERK, and JNK pathways (Narayanan et al., 2008). Adding complexity, modulation of these pathways altered the recruitment of the AR and its cofactors to the PSA enhancer in a ligand-dependent manner. In addition, both SARM and DHT induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases through distinct signaling pathways. These results support the potential utilization of signaling pathways available in a tissue microenvironment to promote maximal stimulation of the AR by various ligands.
    Potential clinical uses of SARMs Muscle-wasting disorders. Adults over 40 years of age lose about 1% muscle mass each year (Carmeli et al., 2002). With life expectancy increasing around the globe, the number of people with compromised muscle mass and accordingly deficits in physical function has increased in the last decade. Age-related muscle wasting or sarcopenia (Bosy-Westphal et al., 2003) and muscle wasting due to cancer, also called cancer cachexia (Dobs et al., 2013), are two serious muscle wasting disorders with no treatment options. Sarcopenia is a major cause of frailty and carries with it an increase in physical disability as well as morbidity and mortality (Muhlberg and Sieber, 2004). The demographic that is widely affected by cancer is adults over 60 years of age. This age-group, already at higher risk to be deficient in muscle due to age-related decline, is then at high risk to lose additional muscle due as their cancer progresses and they receive anti-cancer therapy. Advanced cancer patients lose up to 1.5 kg of lean mass per year (Wallengren et al., 2015). Studies have also demonstrated that muscle mass directly correlates with survival in cancer patients (Liu et al., 2016, Chu et al., 2016). Androgens are important for building and maintaining skeletal muscle, and due to their anabolic effects on muscle are considered front-runners in the potential treatment of cancer cachexia and sarcopenia (Crawford et al., 2016, Dalton et al., 2011). SARMs are particularly relevant in this regard due to their tissue-selectivity and potential to provide therapeutic increases in muscle mass with reduced side-effects.