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  • br Summary and future br Introduction Androgen activity is c

    2024-04-18


    Summary and future
    Introduction Androgen activity is critical for a wide range of developmental and physiological responses and is especially important in phosphodiesterase inhibitor male sexual differentiation and maturation. The biological activity of androgens occurs through binding to the androgen receptor (AR) and the androgen-bound androgen receptor functions as a transcription factor to regulate genes involved in a plethora of physiological processes. Therefore, regulation of AR protein phosphodiesterase inhibitor level is important for modulating the biological function of the AR. Several reports have revealed that the ubiquitin-proteasome system (UPS), particularly the E3 ubiquitin ligases often enhance the degradation of the AR and regulate transcription activation [1]. Nevertheless, it has been shown that lysosome inhibition enhanced AR transcriptional activity, and increased lysosomal biogenesis induced by transcription factor EB (TFEB) overexpression decreased AR activity and reduced the amount of AR [2], suggesting that AR activity can be regulated by lysosomes as well. Lysosomes are ubiquitous membrane-bound cell organelles that are the waste bags for macromolecule degradation and contain hydrolytic enzymes, such as cathepsins and other acidic hydrolases to degrade cellular substrates transferred from endosomes or autophagosomes [3]. In addition to the small GTPase Rab7 and homotypic vacuole fusion and vacuole protein sorting (HOPS) complex, which are responsible for the fusion between mature late endosomes and lysosomes [4], the endosomal sorting complex required for transport (ESCRT complex), comprising five distinct complexes (ESCRTs −0, -I, -II and -III, and Vps4) has also been reported to be involved in this fusion event [5]. Tumor susceptibility gene 101 (TSG101), one of the ESCRT-I components, was originally discovered to be a tumor suppressor and functional inactivation of TSG101 gene led to transformation of murine fibroblasts [6]. Recently, however, TSG101 has received attention in lysosomal fusion events because overexpression of TSG101 can rescue the endosome-lysosomal fusion events which are disrupted by MGRN1 depletion [7]. This suggests that the ESCRT complex components not only participate in vacuolar protein sorting and multivesicular body (MVB) formation, but also regulate endosome-lysosome fusion events. Although it has been shown that TSG101 can downregulate AR-mediated transactivation [8], whether TSG101 can interact with the AR and affect AR expression is not well characterized. In the present study, we demonstrated that TSG101 interacts with the AR and overexpression of TSG101 reduces AR protein level resulting in AR transactivation activity downregulation in LNCaP cells. Further analysis indicated AR protein reduction through TSG101 ectopic expression is due to AR sequestration to TSG101-associated late endosomes followed by lysosomal degradation. Therefore, we have demonstrated that TSG101 has a novel role mediating AR expression regulation via the endosome-lysosomal degradation pathway.
    Materials and methods
    Results
    Discussion The AR plays a critical role in the growth, proliferation and differentiation of prostate cells, but aberrant elevation of AR expression level or its transactivation activity drives the initiation, development and progression of prostate cancer (PCa) as well as its recurrence after chemotherapy [16]. Androgen deprivation therapy (ADT) is, therefore, a priority therapy for androgen-dependent prostate cancer. However, the existing cancer cells eventually become resistant to ADT resulting in castration resistant prostate cancer (CRPC) [17], which is usually caused by abnormal AR reactivation restoring the AR signaling pathway activity. Given the fact that the AR signaling pathway is crucial in disease progression and decreasing AR levels in PCa cells is the primary therapeutic strategy for this malignancy, AR expression regulation has become an important therapeutic target. Here we demonstrated a novel pathway for AR expression regulation in which ectopically expressed TSG101 harnesses the endosome-lysosome system for AR degradation.