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  • 25-hydroxyvitamin d3 In our study we provide evidence for th

    2023-09-18

    In our study we provide evidence for the existence of an endosome-lysosomal pathway for the proteolytic degradation of AR triggered by its interaction with the ESCRT-I component TSG101. The following findings of this study support this notion: (1) We showed that TS101 interacts with endogenous or ectopically expressed AR using a co-immunoprecipitation approach (Fig. 1). We do not, however, exclude the possibility of other proteins mediating the interaction between TSG101 and the AR, because thus far there is no conclusive evidence demonstrating the direct interaction between AR and TSG101 by GST-pull down assay [8]. (2) We showed that TSG101 overexpression in the prostate cancer cell line LNCaP or double expression of TSG101 and AR in AR negative 25-hydroxyvitamin d3 reduced the AR expression level (Fig. 2A), notably that obtained from the cytosolic fraction (Fig. 2D) which resulted in AR-mediated transactivation downregulation and the reduced expression of PSA (Fig. 2C). It appears that TSG101-induced cytosolic AR degradation in LNCaP would be an alternative regulation pathway to downregulate AR activity in the CRPC. (3) We characterized the nature of TSG101-decorated vesicles that are associated with late endosomes/lysosomes, and AR was identified in Lamp2 positive TSG101 vesicles upon treatment with lysosomal protease inhibitors (Fig. 3, Fig. 4A). Moreover, the attenuation of AR expression level induced by TSG101 overexpression can be reverted with inhibitors to lysosomal function (Fig. 4B). It is generally accepted that AR degradation occurs mainly through the proteasomal pathway and previous studies showed that some E3 ligases including MDM2, CHIP and SKP2 [1] bind to the AR and cause AR poly-ubiquitination followed by proteasome degradation. Interestingly, our data indicate the AR may well be subject to proteolysis regulation via lysosome degradation mediated by TSG101 interaction without depending solely on the proteasome pathway.
    Acknowledgements We thank Dr. Ian P. Whitehead (NJMS-UH Cancer Center, New Jersey) for myc-TSG101/pAX142 plasmid; Dr. Rosemary B. Cornell (Simon Fraser University, Canada) for pAX142 vector; Dr. Horng-Heng Juang (Chang Gung University, Taiwan) for LNCaP, PC3 and PC3-AR cell lines, AR/pCDNA3 and pbGL3-PSABHE plasmids and Dr. Hong-Yo Kang (Chang Gung University, Taiwan) for helpful discussions and suggestions. This work was supported in part by Chang Gung Memorial Hospital (CMRPD1F0212 and CMRPD1F0213) and the Ministry of Science and Technology, R.O.C, Taiwan. (MOST104-2320-B-182-011-MY3).
    Introduction The androgens testosterone and dihydrotestosterone act through the androgen receptor (AR). Testosterone is produced by the Leydig cells of the testes and the theca cells of the ovaries and the weaker androgen, dehydroepiandrosterone, is synthesised in the adrenal gland of both men and women (Smith et al., 2013). Testosterone acts as both a hormone and a pro-hormone, being converted to its more powerful derivative dihydrotestosterone (DHT) by 5-α-reductase in peripheral tissues (skin, hair follicle, bone, prostate, liver) or by aromatase to the potent oestrogen, 17β-oestradiol (ovaries, bone, brain, adipose tissue, prostate) (reviewed in Smith et al., 2013, Li and Rahman, 2008, Ellem and Risbridger, 2010). DHT has two fold greater affinity for the AR and a five-fold lower rate of dissociation than testosterone (Grino et al., 1990). The levels of circulating androgens decline with age in both sexes, which can impact on bone and muscle integrity, sexual drive and general wellbeing. In addition, the expression and activity of the AR has been shown to play an important role in the development or progression of a number of cancers (prostate, breast, endometrial, bladder, kidney) (Ma et al., 2008, Chang et al., 2014, Godoy et al., 2016) and a range of other conditions including acne, male-pattern baldness and polycystic ovarian syndrome (Smith et al., 2013). The AR is expressed ubiquitously in human and mouse tissues, although the amount of the mRNA varies, with the highest levels reported for reproductive tissues (testes, prostate, ovaries, uterus), liver, breast, adipose and muscle (see Ruizeveld de Winter et al., 1991, Kumar and Thakur, 2004, Bookout et al., 2006; Human Protein Atlas [www.proteinatlas.org]). Despite considerable efforts to identify regulatory sequences in the promoter region and within the coding sequence of the AR gene a comprehensive understanding of the mechanisms controlling expression of the receptor mRNA and protein in different target tissues is lacking. In this review we will consider recent developments and discuss these in the context of older literature to better understand the regulatory networks controlling tissue-selective expression of androgen receptor levels. Our main focus will be on breast and bone and include comparisons with the prostate gland where appropriate.