Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1<i>α</i> Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

Fernandez, Elena V.; Reece, Kelie; Ley, Ariel M.; Troutman, Sarah M.; Sissung, Tristan M.; Price, Douglas K.; Chau, Cindy H.; Figg, William D.

doi:10.1124/mol.114.097477

Cited by 59 publications

(55 citation statements)

References 26 publications

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“…7, 28, 29 Since increased PHF8 expression has been reported to occur broadly in prostate cancer, we hypothesized that increased PHF8 expression in prostate cancer could be at least partly induced by hypoxia. To test this hypothesis, we cultured three prostate cancer cell lines, LNCaP, 22RV1 and DU145 under hypoxic conditions for 0, 12 and 24 h and then examined the levels of PHF8 protein by western blot analysis and mRNA by RT–PCR.…”

Section: Resultsmentioning

confidence: 99%

The HIF/PHF8/AR axis promotes prostate cancer progression

Tong

Liu

et al. 2016

Oncogenesis

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Recent studies provide strong evidence that the androgen receptor (AR) signaling pathway remains active in castration-resistant prostate cancer (CRPC). However, the underlying mechanisms are not well understood. In this study, we demonstrate that plant homeo domain finger protein 8 (PHF8 )interacts with and functions as an essential histone demethylase activity-dependent AR coactivator. Furthermore, we demonstrate that the expression of PHF8 is induced by hypoxia in various prostate cancer cell lines. Knockdown of either hypoxia-inducible factor HIF2α or HIF1α almost completely abolished hypoxia-induced PHF8 expression. Importantly, we observed that PHF8 is highly expressed in clinical androgen deprived prostate cancer samples and expression of PHF8 correlates with increased levels of HIF1α and HIF2α. Moreover, elevated PHF8 is associated with higher grade prostate cancers and unfavorable outcomes. Our findings support a working model in which hypoxia in castrated prostate cancer activates HIF transcription factors which then induces PHF8 expression. The elevated PHF8 in turn promotes the AR signaling pathway and prostate cancer progression. Therefore, the HIF/PHF8/AR axis could serve as a potential biomarker for CRPC and is also a promising therapeutic target in combating CRPC.

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Section: Resultsmentioning

confidence: 99%

The HIF/PHF8/AR axis promotes prostate cancer progression

Tong

Liu

et al. 2016

Oncogenesis

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“…More experiments need to be conducted Our data demonstrated a potentially synergistic inhibitory effect of the combination of PPI and enzalutamide on CRPC cell growth and relevant molecular targets. Enzalutamide combined with other agents exhibited even greater inhibitory effects on CRPC cells via multiple molecular mechanisms [53][54][55][56]. In addition, PPI was reported to reverse epithelialmesenchymal transition, decrease the expression levels of interleukin-6 and signal transducer activator of transcription 3 (STAT3) in the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib-resistant lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Xiang

Zou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.

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“…Considering the seven genes identified in this study are upregulated by androgen, HIF1a and/or hypoxia it is hypothesized that they promote disease progression and development of CRPC and it would be interesting to look at the expression of these genes in high risk and advanced prostate cancer cohorts. As AR and HIF signaling axes are active in CRPC these seven genes are potential biomarkers of aggressive disease that might be useful to predict likely disease progression towards CRPC [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Independence of HIF1a and androgen signaling pathways in prostate cancer

Tran

Bibby

Yang

et al. 2019

Preprint

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Androgen signaling drives prostate cancer progression and is a therapeutic target.Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.

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Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

Cited by 59 publications

References 26 publications

The HIF/PHF8/AR axis promotes prostate cancer progression

The HIF/PHF8/AR axis promotes prostate cancer progression

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Independence of HIF1a and androgen signaling pathways in prostate cancer

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