Androgen and Its Receptor Promote Bax-Mediated Apoptosis

Lin, Yu-Ting; Kokontis, John M.; Tang, Fangming; Godfrey, Bradley; Liao, Shutsung; Lin, Anning; Chen, Youting; Xiang, Jialing

doi:10.1128/mcb.26.5.1908-1916.2006

Cited by 71 publications

(70 citation statements)

References 68 publications

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“…In addition, both DT and VAT AR mRNA positively correlated with VAT expression of the proapoptotic gene BAX. The promotion of BAX-mediated apoptosis by androgen and its receptor has been already reported in different cellular systems (Lin et al 2006), but not fully investigated in this study. Whether the induction of apoptotic processes could be an additional mechanism through which testosterone counteracts VAT expansion in MetS rabbits remains to be demonstrated.…”

Section: Discussionmentioning

confidence: 81%

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Maneschi¹,

Morelli²,

Filippi³

et al. 2012

Journal of Endocrinology

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We recently demonstrated that testosterone dosing ameliorated the metabolic profile and reduced visceral adipose tissue (VAT) in a high-fat diet (HFD)-induced rabbit model of metabolic syndrome (MetS). We studied the effects of HFD and in vivo testosterone dosing on VAT function and the adipogenic capacity of rabbit preadipocytes isolated from VAT of regular diet (RD), HFD, and testosterone-treated HFD rabbits. VAT was studied by immunohistochemistry, western blot, and RT-PCR. Isolated rPADs were exposed to adipocyte differentiating mixture (DIM) to evaluate adipogenic potential. Adipocyte size was significantly increased in HFD VAT compared with RD, indicating adipocyte dysfunction, which was normalized by testosterone dosing. Accordingly, perilipin, an anti-lipolytic protein, was significantly increased in HFD VAT, when compared with other groups. HFD VAT was hypoxic, while testosterone dosing normalized VAT oxygenation. In VAT, androgen receptor expression was positively associated with mRNA expression of GLUT4 (SLC2A4) (insulin-regulated glucose transporter) and STAMP2 (STEAP4) (androgen-dependent gene required for insulin signaling). In testosterone-treated HFD VAT, STAMP2 mRNA was significantly increased when compared with the other groups. Moreover, GLUT4 membrane translocation was significantly reduced in HFD VAT, compared with RD, and increased by testosterone. In DIM-exposed preadipocytes from HFD, triglyceride accumulation, adipocyte-specific genes, insulin-stimulated triglyceride synthesis, glucose uptake, and GLUT4 membrane translocation were reduced compared with preadipocytes from RD and normalized by in vivo testosterone dosing. In conclusion, testosterone dosing in a MetS animal model positively affects VAT functions. This could reflect the ability of testosterone in restoring insulin sensitivity in VAT, thus counteracting metabolic alterations.

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Section: Discussionmentioning

confidence: 81%

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Maneschi¹,

Morelli²,

Filippi³

et al. 2012

Journal of Endocrinology

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“…In this type of apoptosis, two proapoptotic proteins, Bid and Bax, play a crucial role in intracellular signal transduction [46]. In AR-positive prostate cancer cells, it has been demonstrated that androgens and AR promote stress-mediated apoptosis via augmentation of Bax translocation to the mitochondria and upregulation of Noxa protein expression [47]. Moreover, it has been shown that another nonsteroidogenic androgen antagonist, casodex [48], induces apoptosis in AR-positive human prostate tumor cells line LNCaP, suggesting that androgen may be required for cell survival [49].…”

Section: Discussionmentioning

confidence: 99%

Does 2-hydroxyflutamide Inhibit Apoptosis in Porcine Granulosa Cells? — An <i>In Vitro</i> Study

Duda

Durlej

Knet

et al. 2012

Journal of Reproduction and Development

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Abstract. In mammalian ovaries, the majority of follicles are lost before ovulation by atresia. This degenerative process is initiated or caused by granulosa cell apoptosis. To reveal the androgen-dependent mechanism of selective follicular atresia, the culture model system for agonism and antagonism of the androgen receptor has been established. We examined the influence of an androgen receptor antagonist, 2-hydroxyflutamide (2-Hf), on the incidence of apoptosis in cultured porcine granulosa cells. They were incubated (6 and 12-h) in the presence of testosterone (T, 10 -7 M), 2-Hf (1.7×10 -4 M) or both T and 2-Hf (T+2-Hf), and then analyzed by flow cytometry with fluorescein labelled annexin V. To better imitate in vivo conditions, the intact porcine follicles (6-8 mm in diameter) have been incubated in an organ culture system with the addition of the same factors. Sections obtained from follicles fixed after culture were stained with hematoxylin and eosin, and the presence of apoptosis-related DNA strand breaks was evaluated by the TUNEL method. Estradiol and progesterone concentrations in the culture media were measured by radioimmunoassays. The addition of T or 2-Hf to the culture media caused an increase in the number of apoptotic granulosa cells, while treatment with T+2-Hf decreased it in both in vitro and organotypic models. Follicles cultured with the addition of T or 2-Hf exhibited morphological changes indicating follicular atresia. Granulosal estradiol secretion was considerably stimulated by T+2-Hf. The highest increase in follicular estradiol secretion was observed after the anti-androgen addition. In both granulosal and follicular cultures, the production of progesterone declined in the presence of T or 2-Hf but increased after their simultaneous addition. In conclusion, androgen receptor antagonist 2-Hf attenuates induction of granulosa cell apoptosis in the presence of a high T level. The nature of this protective mechanism as yet is unknown and requires further research. Key words: Apoptosis, Granulosa cells, 2-hydroxyflutamide, Ovarian follicles, Pig (J. Reprod. Dev. 58: [438][439][440][441][442][443][444] 2012) T he ovary plays two distinct functions in female reproduction: it produces germ cells (oocytes) and provides a proper hormonal environment for ovarian follicles undergoing cycles of growth and development induced by gonadotropins [1][2][3]. Although gonadotropins are predominant regulators of follicular development, it is now clear that there is a wide range of additional regulators of follicular maturation produced within the ovarian tissue such as steroids and peptide hormones, as well as ovarian growth factors. They act by paracrine mechanisms to modulate, either to amplify or attenuate, the functions of gonadotropins [4]. Amongst the several hundred thousand primordial follicles present in the mammalian ovary, only 1% of them develop to the preovulatory stage and finally ovulate [5]. The remaining ones will be eliminated via a degenerative process called atresia [6,7]. Atresia ...

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“…Interestingly, studies form Liao and coworkers demonstrate that AR-positive LNCaP cells, conditioned by long-term androgen withdrawal become hypersensitive to androgen and could be suppressed by androgen in vivo 65 and identify decreased cMyc and increased Bax as responsible genes. 66 Moreover. LNCaP sublines rendered androgen-independent, could be suppressed by androgen and then reversed to androgen-dependent phenotype.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

Nelius

Filleur

Yemelyanov

et al. 2007

Intl Journal of Cancer

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The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions. While androgen ablation drives the regression of normal and cancerous prostate, testosterone may cause both proliferation and apoptosis. Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor (AR), however no mechanistic explanation was offered. In this paper we demonstrate in vivo anti-tumor effect of the AR on prostate cancer growth and identify its molecular mediators. We analyzed the effect of AR on the tumorigenicity of prostate cancer cells. Unexpectedly, the AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls. Moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis. AR expression lowered the angiogenic potential of cancer cells, by increasing secretion of an anti-angiogenic protein, thrombospondin-1. AR activation caused a decrease in RelA, a subunit of the pro-survival transcription factor NFjB, reduced its nuclear localization and transcriptional activity. This, in turn, diminished the expression of its anti-apoptotic targets, Bcl-2 and IL-6. Increased apoptosis within AR-expressing tumors was likely due to the NFjB suppression, since it was restricted to the cells lacking nuclear (active) NFjB. Thus we for the first time identified combined decrease of NFjB and increased TSP1 as molecular events underlying the AR anti-tumor activity in vivo. Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal, a standard treatment for early-stage prostate cancer. ' 2007 Wiley-Liss, Inc.

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Androgen and Its Receptor Promote Bax-Mediated Apoptosis

Cited by 71 publications

References 68 publications

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Does 2-hydroxyflutamide Inhibit Apoptosis in Porcine Granulosa Cells? — An <i>In Vitro</i> Study

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

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