Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer

Kashiwagi, Eiji; Ide, Hiroki; Inoue, Satoshi; Kawahara, Takashi; Zheng, Yian; Reis, Leonardo Oliveira; Baras, Alexander S.; Miyamoto, Hiroshi

doi:10.18632/oncotarget.9994

Cited by 58 publications

(93 citation statements)

References 45 publications

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“…al. showed that AR activation induces chemoresistance in bladder cancer, possibly by modulating NF-κB [36]. These findings support the idea that both androgens and AR are possibly involved in bladder cancer, which may be linked to repression of the UGT isozymes.…”

Section: Nuclear Receptor Regulation Of Ugt Expression In Bladder Cancersupporting

confidence: 69%

Glucuronidation and UGT isozymes in bladder: new targets for the treatment of uroepithelial carcinomas?

2016

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Bladder cancer has been linked to numerous toxins which can be concentrated in the bladder after being absorbed into the blood and filtered by the kidneys. Excessive carcinogenic load to the bladder urothelium may result in the development of cancer. However, enzymes within the bladder can metabolize carcinogens into substrates that are safer. Importantly, these proteins, namely the UGTs (uridine 5-diphospho-glucuronosyltransferases), have been shown to possibly prevent bladder cancer. Also, studies have shown that the UGT1 expression is decreased in uroepithelial carcinomas, which may allow for the accumulation of carcinogens in the bladder. In this review, we discuss the UGT system and its protective role against bladder cancer, UGT genetic mutations that modulate risk from chemicals and environmental toxins, as well as targeting of the UGT enzymes by nuclear receptors.

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Section: Nuclear Receptor Regulation Of Ugt Expression In Bladder Cancersupporting

confidence: 69%

Glucuronidation and UGT isozymes in bladder: new targets for the treatment of uroepithelial carcinomas?

2016

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“…Non-androgen-mediated AR activation in bladder cancer cells [23] and androgen-induced tumorigenesis via the non-AR pathway [14] have also been documented. Moreover, AR activation has been correlated with resistance to chemotherapy in bladder cancer cells [24, 25]. In contrast, estrogens likely exert both stimulatory and inhibitory actions on bladder cancer outgrowth, which may be cell-specific and/or dependent on the functional activity of ERα and ERβ [11, 12, 26–32].…”

Section: Introductionmentioning

confidence: 99%

Histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: A meta-analysis of immunohistochemical studies

2017

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ObjectiveEmerging preclinical evidence suggests the involvement of sex hormones and their receptor signals in the development and progression of bladder cancer. Meanwhile, previous studies have demonstrated conflicting results on the relationship between the status of sex hormone receptors in urothelial tumors and histopathological characteristics of the tumors or patient outcomes. We therefore conducted this meta-analysis to assess the clinicopathological impact of the expression of androgen receptor (AR) and estrogen receptors (ERs) in bladder cancer.MethodsA comprehensive literature search in databases (i.e. PubMed, Web of Science, Cochrane) was performed for all immunohistochemical studies stained for AR, ERα, and/or ERβ in surgically resected bladder cancer specimens and analyzed for patient outcomes. We selected eligible studies in accordance with the PRISMA guidelines and analyzed data using R software.ResultsA total of 2,049 patients from 13 retrospective studies were included in this meta-analysis. The difference in ERα expression between non-tumors and tumors was significant [odds ratio (OR) = 0.412; P<0.001], while those of AR (OR = 3.256; P = 0.336) or ERβ (OR = 0.580; P = 0.674) were not statistically significant. AR positivity in tumors was strongly correlated with gender (male vs. female: OR = 0.658; P = 0.027) or tumor grade (low-grade vs. high-grade: OR = 0.575; P<0.001). ERβ positive rates were significantly higher in high-grade (OR = 2.169; P<0.001) and muscle-invasive (OR = 3.104; P<0.001) tumors than in low-grade and non-muscle-invasive tumors, respectively. Survival analysis in patients with non-muscle-invasive bladder cancer revealed associations between AR expression and better recurrence-free survival [hazard ration (HR) = 0.593; P = 0.006) as well as between ERβ expression and worse recurrence-free (HR = 1.573; P = 0.013) or progression-free (HR = 4.148; P = 0.089) survivals.ConclusionsThese data suggest down-regulation of ERα expression in bladder tumors, compared with non-neoplastic urothelial tissues. AR or ERβ expression was down- or up-regulated, respectively, in high-grade and/or muscle-invasive bladder cancers. Moreover, immunohistochemistry of AR/ERβ in surgical specimens may serve as prognosticators in patients with non-muscle-invasive bladder tumor.

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“…5). We have further demonstrated that androgens activate EGFR/Akt (6) and NFkB (7,8) signals in AR-positive bladder cancer cells.…”

Section: Introductionmentioning

confidence: 51%

“…Human urothelial cancer cell lines, UMUC3 and 5637, were originally obtained from the ATCC. Another human urothelial cancer cell line, 647V, was used in our previous studies (7,8,(13)(14)(15)(16)(17)(18). All these lines were recently authenticated, using GenePrint 10 System (Promega), by the institutional core facility, and routinely tested for mycoplasma contamination using PCR Mycoplasma Detection Kit (Applied Biological Materials Inc.).…”

Section: Cell Culturementioning

confidence: 99%

“…Meanwhile, the levels of AR mRNA/protein were elevated in bladder cancer sublines resistant to radiotherapy compared with control lines and its expression in urothelial cancer may therefore serve as a predictor of radioresistance. Moreover, because AR activation has also been shown to contribute to chemoresistance (7,15,26), chemoradiation combined with ADT may represent an ideal treatment for locally advanced AR-positive bladder cancer as the alternative to current standard therapy including radical cystectomy. Nonetheless, methods of anti-AR therapy and their optimal dose/timing in urothelial cancer treatment should be further investigated.…”

Section: Figurementioning

confidence: 99%

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Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer

Ide

Inoue

Mizushima

et al. 2018

Molecular Cancer Therapeutics

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Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR-positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4-24 hours after irradiation. We then established "radiation-resistant" sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as , and, in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer. .

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Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer

Cited by 58 publications

References 45 publications

Glucuronidation and UGT isozymes in bladder: new targets for the treatment of uroepithelial carcinomas?

Glucuronidation and UGT isozymes in bladder: new targets for the treatment of uroepithelial carcinomas?

Histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: A meta-analysis of immunohistochemical studies

Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer

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