Androgen and anti-androgen treatment modulates androgen receptor activity and DJ-1 stability

Pitkänen-Arsiola, Tiina; Tillman, Janet; Gu, Guangyu; Yuan, Jianyong; Roberts, Richard L.; Wantroba, Marcus; Coetzee, Gerhard A.; Cookson, Michael S.; Kasper, Susan

doi:10.1002/pros.20450

Cited by 30 publications

(32 citation statements)

References 31 publications

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“…Previously, we showed that antiandrogen treatment could stimulate AR-regulated signaling in a subpopulation of HPE cells cultured from prostate biopsy specimens (11). Proteomic analysis identified DJ-1 as a protein whose expression was up-regulated by both androgen and antiandrogen treatment and that this increase was due to DJ-1 and AR protein stability.…”

Section: Introductionmentioning

confidence: 92%

“…Western blot analysis confirmed this result, showing that DJ-1 and AR protein levels increased following treatment with dihydrotestosterone (DHT), the synthetic androgen R1881, or the antiandrogen hydroxy-flutamide (OH-flutamide) in LNCaP cells. Blocking protein synthesis with cycloheximide revealed that the increase in DJ-1 was due to increased protein stability (11). This indicated that DJ-1 and AR expression was regulated by both androgens and antiandrogen therapy and may be involved in AIPC.…”

Section: Introductionmentioning

confidence: 96%

“…To this end, a proteomic analysis of primary human prostate epithelial (HPE) cells after treatment with the antiandrogen flutamide was done (11). DJ-1 was identified as one protein that increased during flutamide treatment.…”

Section: Introductionmentioning

confidence: 99%

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DJ-1 Binds Androgen Receptor Directly and Mediates Its Activity in Hormonally Treated Prostate Cancer Cells

Tillman

Yuan²,

Gu³

et al. 2007

Cancer Research

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The oncogene DJ-1 has been associated with multiple cancers, including prostate cancer, where it can be stabilized by androgens and antiandrogens. However, little data exist on the expression pattern and function of DJ-1 in prostate cancer. To address the function of DJ-1 in prostate, a yeast two-hybrid screen was done to identify novel DJ-1 binding proteins. The androgen receptor (AR) was identified and confirmed as a DJ-1 binding partner. This is the first evidence that DJ-1 directly interacts with AR. We also show that modulation of DJ-1 expression regulated AR transcriptional activity. Importantly, both the subcellular localization of DJ-1 and the interaction with AR are regulated by androgens and antiandrogens.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 96%

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DJ-1 Binds Androgen Receptor Directly and Mediates Its Activity in Hormonally Treated Prostate Cancer Cells

Tillman

Yuan²,

Gu³

et al. 2007

Cancer Research

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“…The LNCaP human prostate cancer cell line was obtained from American type culture collection and was cultured as described by Pitk€ anen-Arsiola et al 54 LNCaP cells were grown in 10 cm plates and when they are 80% confluence, the cells are stained with the green fluorescent chloromethyl derivatives of fluorescein diacetate (CMFDA). The cells were stained following manufacturer's protocol (MP02925, Life Technology, Inc.).…”

Section: Protocolsmentioning

confidence: 99%

Modulation of rotation-induced lift force for cell filtration in a low aspect ratio microchannel

et al. 2014

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Cell filtration is a critical step in sample preparation in many bioapplications. Herein, we report on a simple, filter-free, microfluidic platform based on hydrodynamic inertial migration. Our approach builds on the concept of two-stage inertial migration which permits precise prediction of microparticle position within the microchannel. Our design manipulates equilibrium positions of larger microparticles by modulating rotation-induced lift force in a low aspect ratio microchannel. Here, we demonstrate filtration of microparticles with extreme efficiency (>99%). Using multiple prostate cell lines (LNCaP and human prostate epithelial tumor cells), we show filtration from spiked blood, with 3-fold concentration and >83% viability. Results of a proliferation assay show normal cell division and suggest no negative effects on intrinsic properties. Considering the planar low-aspect-ratio structure and predictable focusing, we envision promising applications and easy integration with existing lab-on-a-chip systems. V C 2014 AIP Publishing LLC.

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“…A few investigators have analyzed mechanisms underlying AWS other than mutations of AR gene (16)(17)(18). Pitkänen-Arsiola et al reported that stabilization of AR and its co-regulator, DJ-1, in the absence of androgen may partially account for AWS (16).…”

Section: Discussionmentioning

confidence: 99%

The antiandrogen bicalutamide activates the androgen receptor (AR) with a mutation in codon 741 through the mitogen activated protein kinase (MARK) pathway in human prostate cancer PC3 cells

Miyake¹

2010

Oncol Rep

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Abstract. The objective of this study was to assess the effect of antiandrogen on the activation of mutated androgen receptor (AR) and its signaling pathway in prostate cancer. We transfected the AR gene with a point mutation at codon 741 (tryptophan to leucine; W741L) into human androgenindependent prostate cancer PC3 cells lacking the expression of AR, and established PC3 cells overexpressing mutant type AR (PC3/W741L). Changes in the phenotype in these cells were compared to those in PC3 cells transfected with wildtype AR (PC3/Wild) and control vector alone (PC3/Co). There was no significant differences in the growth among PC3/Co, PC3/Wild and PC3/W741L cells. A transactivation assay using these cells showed that bicalutamide activated W741L mutant type AR, but not wild-type AR, while hydroxyflutamide failed to activate either type of ARs. Treatment with specific inhibitors of the MAPK or STST3 pathway (UO126 or AG490, respectively), in contrast to treatment with the Akt pathway inhibitor LY294002, significantly inhibited the dihydrotestosterone-induced activation of both wild-type and mutant ARs; however, activation of W741L mutant AR by bicalutamide was significantly inhibited by treatment with UO126, in contrast to treatment with AG490 or LY294002. Furthermore, treatment of PC3/W741L with bicalutamide, in contrast to treatment with hydroxyflutamide, resulted in significant upregulation of phosphorylated p44/42 MAPK. These findings suggest that the MAPK pathway might be involved in the activation of the AR with a point mutation at codon 741 induced by treatment with the antiandrogen bicalutamide. IntroductionProstate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer-specific deaths in men in Western industrialized countries. Despite intensive efforts in the field of prostate cancer research, androgen withdrawal therapy has continued to be the mainstay of treatment for men with advanced prostate cancer since the report by Huggins and Hodges in 1941 (1). In recent years, a novel therapeutic strategy of androgen ablation by combining luteinizing hormone-releasing hormone analog and antiandrogen was introduced as 'maximal androgen blockade (MAB)'. Initially, ~90% of patients with advanced prostate cancer favorably respond to MAB therapy; however, androgenindependent (AI) progression ultimately occurs within a few years in the majority of these patients (1,2). During the course of AI progression, a paradoxical phenomenon, 'antiandrogen withdrawal syndrome (AWS)', which is characterized by the improvement of clinical findings associated with prostate cancer following discontinuation of therapeutic antiandrogen, has been shown to occur in 25-50% of patients treated with androgen ablation therapy (3,4).Several investigators have reported the activation of some types of mutant androgen receptors (ARs) by anti-androgens (5-9). For example, Fenton et al reported that flutamide works as an agonist for T877S and H874Y mutant ARs (6), while Hara et al showed the stimulation of W741...

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Androgen and anti-androgen treatment modulates androgen receptor activity and DJ-1 stability

Abstract: Stabilization of AR and its co-regulators in the absence of androgen may partially account for anti-androgen withdrawal syndrome and potentially contribute to the development of hormone refractory PCa.

Cited by 30 publications

References 31 publications

DJ-1 Binds Androgen Receptor Directly and Mediates Its Activity in Hormonally Treated Prostate Cancer Cells

DJ-1 Binds Androgen Receptor Directly and Mediates Its Activity in Hormonally Treated Prostate Cancer Cells

Modulation of rotation-induced lift force for cell filtration in a low aspect ratio microchannel

The antiandrogen bicalutamide activates the androgen receptor (AR) with a mutation in codon 741 through the mitogen activated protein kinase (MARK) pathway in human prostate cancer PC3 cells

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