Prx1 Enhances Androgen Receptor Function in Prostate Cancer Cells by Increasing Receptor Affinity to Dihydrotestosterone

Chhipa, Rishi Raj; Lee, Kwang‐Soon; Oñate, Sergio A.; Wu, Yue; Ip, Clement

doi:10.1158/1541-7786.mcr-08-0546

Cited by 43 publications

(35 citation statements)

References 44 publications

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“…Second line chemotherapy with docetaxel is only effective in 30–50% of patients (Tannock et al , 2004). PRDX-1 is known to interact with the androgen receptor, enhancing ligand binding and regulating transactivation of androgen-regulated genes (Park et al , 2007; Chhipa et al , 2009; Shiota et al , 2011; Miki and Funato, 2012; Ray et al , 2012). …”

mentioning

confidence: 99%

Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress

Whitaker¹,

Patel²,

Howat³

et al. 2013

Br J Cancer

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Objective:We have previously identified peroxiredoxin-3 (PRDX-3) as a cell-surface protein that is androgen regulated in the LNCaP prostate cancer (PCa) cell line. PRDX-3 is a member of the peroxiredoxin family that are responsible for neutralising reactive oxygen species.Experimental design:PRDX-3 expression was examined in tissue from 32 patients using immunohistochemistry. Subcellular distribution was determined using confocal microscopy. PRDX-3 expression was determined in antiandrogen-resistant cell lines by western blotting and quantitative RT–PCR. The pathways of PRDX-3 overexpression and knockdown on apoptosis and response to oxidative stress were investigated using protein arrays.Results:PRDX-3 is upregulated in a number of endocrine-regulated tumours; in particular in PCa and prostatic intraepithelial neoplasia. Although the majority of PRDX-3 is localised to the mitochondria, we have confirmed that PRDX-3 at the cell membrane is androgen regulated. In antiandrogen-resistant LNCaP cell lines, PRDX-3 is upregulated at the protein but not RNA level. Resistant cells also possess an upregulation of the tricarboxylic acid (TCA) pathway and resistance to H2O2-induced apoptosis through a failure to activate pro-apoptotic pathways. Knockdown of PRDX-3 restored H2O2 sensitivity.Conclusion:Our results suggest that PRDX-3 has an essential role in regulating oxidation-induced apoptosis in antiandrogen-resistant cells. PRDX-3 may have potential as a therapeutic target in castrate-independent PCa.

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mentioning

confidence: 99%

Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress

Whitaker¹,

Patel²,

Howat³

et al. 2013

Br J Cancer

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“…The pSilencer 5.1 system (Ambion, Austin, TX, USA) was used for the expression of Prx1-targeted shRNA. Sense and antisense oligonucelotide sequences targeting human Prx1, as well as a scrambled control, were described by Chhipa et al23. The specificity of both shRNA sequences and the scrambled sequences was confirmed by searching the genome database (BLAST).…”

Section: Methodsmentioning

confidence: 99%

Elevated Prx1 Provides Resistance to Docetaxel, But Is Not Associated with Predictive Significance in Lung Cancer

et al. 2013

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BackgroundThis study was conducted in order to elucidate the effects of docetaxel on the growth of peroxiredoxin 1 (Prx1) knockdown A549 xenograft tumors and further tested the role of Prx1 as a predictor for how a patient would respond to docetaxel treatment.MethodsEffects of docetaxel on the growth of scrambled- and shPrx1-infected A549 xenograft tumors in nude mice were measured. Moreover, immunohistochemical expression of Prx1 was evaluated in paraffin-embedded tissues from 24 non-small cell lung cancer patients who had received docetaxel-cisplatin regimens as a first-line treatment.ResultsDocetaxel treatment in Prx1 knockdown xenograft tumor resulted in reduced tumors growth compared with other groups. Prx1 knockdown increased the production of cleaved caspases-8 and -9 in the control itself compared to scramble tumors. Moreover, docetaxel treatment in Prx1 knockdown tissue led to an increased protein band. Phosphorylated Akt was found in Prx1 scramble tissues. Phosphorylated FOXO1 was detected in the docetaxel treatment group. On the other hand, Prx1 knockdown completely suppressed the Akt-FOXO1 axis. The median progression-free survival (PFS) of patients with low Prx1 expression was 7 months (95% confidence interval [CI], 6.0-7.7), whereas the median progression-free survival of patients with high Prx1 expression was 4 months (95% CI, 4.0-5.0). However, high Prx1 expression was not associated with decreased PFS (p=0.114).ConclusionOur findings suggest that elevated Prx1 provides resistance to docetaxel treatment through suppression of FOXO1-induced apoptosis in A549 xenograft tumors, but may not be related with the predictive significance for response to docetaxel treatment.

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“…Whole cell 3 H-DHT binding assay was performed by using a previously described method with some modification. 7 Cells were plated at 50,000 cells per well in ©2 0 1 1 L a n d e s B i o s c i e n c e . D o n o t d i s t r i b u t e .…”

Section: Methodsmentioning

confidence: 99%

“…Our previous work showed that Prx1 knockdown significantly decreases the DHT-binding affinity of AR. 7 This effect may contribute favorably to boost the response to finasteride. To test the hypothesis, LNCaP cells were transfected with Prx1 siRNA or scrambled siRNA.…”

confidence: 99%

The antiandrogenic effect of finasteride against a mutant androgen receptor

Chhipa

Zhang

et al. 2011

Cancer Biology & Therapy

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Prx1 Enhances Androgen Receptor Function in Prostate Cancer Cells by Increasing Receptor Affinity to Dihydrotestosterone

Abstract: Androgen receptor (AR) signaling plays a critical role in the development and progression of prostate cancer.

Cited by 43 publications

References 44 publications

Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress

Peroxiredoxin-3 is overexpressed in prostate cancer and promotes cancer cell survival by protecting cells from oxidative stress

Elevated Prx1 Provides Resistance to Docetaxel, But Is Not Associated with Predictive Significance in Lung Cancer

The antiandrogenic effect of finasteride against a mutant androgen receptor

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