Valproic acid synergistically enhances the cytotoxicity of gossypol in DU145 prostate cancer cells: An iTRTAQ-based quantitative proteomic analysis

Ouyang, Dong-Yun; Ji, Yu; Saltis, Mark; Xu, Lihui; Zhang, Yan Ting; Zha, Qing Bing; Cai, Jiye; He, Xian-Hui

doi:10.1016/j.jprot.2011.06.016

Cited by 17 publications

(10 citation statements)

References 57 publications

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“…This points towards a possible novel mechanism how rhBMP-2 and rhBMP-7 fracture therapies in patients could be optimized. Valproic acid is already in clinical use as one of the most common antiepileptic drugs with proposed off-label use as anticancer drug [29,30]. However, it still lacks evaluation in vivo as valproic acid is reported to have severe side effects, for example, embryotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor β1 inhibits bone morphogenic protein (BMP)-2 and BMP-7 signaling via upregulation of Ski-related novel protein N (SnoN): possible mechanism for the failure of BMP therapy?

Ehnert

Zhao

Pscherer

et al. 2012

BMC Med

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BackgroundBone morphogenic proteins (BMPs) play a key role in bone formation. Consequently, it was expected that topical application of recombinant human (rh)BMP-2 and rhBMP-7 would improve the healing of complex fractures. However, up to 36% of fracture patients do not respond to this therapy. There are hints that a systemic increase in transforming growth factor β1 (TGFβ1) interferes with beneficial BMP effects. Therefore, in the present work we investigated the influence of rhTGFβ1 on rhBMP signaling in primary human osteoblasts, with the aim of more specifically delineating the underlying regulatory mechanisms.MethodsBMP signaling was detected by adenoviral Smad-binding-element-reporter assays. Gene expression was determined by reverse transcription polymerase chain reaction (RT-PCR) and confirmed at the protein level by western blot. Histone deacetylase (HDAC) activity was determined using a test kit. Data sets were compared by one-way analysis of variance.ResultsOur findings showed that Smad1/5/8-mediated rhBMP-2 and rhBMP-7 signaling is completely blocked by rhTGFβ1. We then investigated expression levels of genes involved in BMP signaling and regulation (for example, Smad1/5/8, TGFβ receptors type I and II, noggin, sclerostin, BMP and activin receptor membrane bound inhibitor (BAMBI), v-ski sarcoma viral oncogene homolog (Ski), Ski-related novel protein N (SnoN) and Smad ubiquitination regulatory factors (Smurfs)) and confirmed the expression of regulated genes at the protein level. Smad7 and SnoN were significantly induced by rhTGFβ1 treatment while expression of Smad1, Smad6, TGFβRII and activin receptor-like kinase 1 (Alk1) was reduced. Elevated SnoN expression was accompanied by increased HDAC activity. Addition of an HDAC inhibitor, namely valproic acid, fully abolished the inhibitory effect of rhTGFβ1 on rhBMP-2 and rhBMP-7 signaling.ConclusionsrhTGFβ1 effectively blocks rhBMP signaling in osteoblasts. As possible mechanism, we postulate an induction of SnoN that increases HDAC activity and thereby reduces the expression of factors required for efficient BMP signaling. Thus, inhibition of HDAC activity may support bone healing during rhBMP therapy in patients with elevated TGFβ serum levels.

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Section: Discussionmentioning

confidence: 99%

Transforming growth factor β1 inhibits bone morphogenic protein (BMP)-2 and BMP-7 signaling via upregulation of Ski-related novel protein N (SnoN): possible mechanism for the failure of BMP therapy?

Ehnert

Zhao

Pscherer

et al. 2012

BMC Med

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“…It has been recently confirmed that genes and proteins involved in cellular metabolism play a crucial part in the development and progression of PC (Pettazzoni et al, 2011;Ouyang et al, 2011). Glycolysis/Gluconeogenesis pathway belongs to the lipid metabolism.…”

Section: Metabolism Pathwaysmentioning

confidence: 99%

Key pathways involved in prostate cancer based on gene set enrichment analysis and meta analysis

Ning¹,

Wu²,

Zang³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. Prostate cancer is one of the most common male malignant neoplasms; however, its causes are not completely understood. A few recent studies have used gene expression profiling of prostate cancer to identify differentially expressed genes and possible relevant pathways. However, few studies have examined the genetic mechanics of prostate cancer at the pathway level to search for such pathways. We used gene set enrichment analysis and a meta-analysis of six independent studies after standardized microarray preprocessing, which increased concordance between these gene datasets. Based on gene set enrichment analysis, there were 12 down-and 25 up-regulated mixing pathways in more than two tissue datasets, while there were two down-and two up-regulated mixing pathways in three cell datasets. Based on the meta-analysis, there were 46 and nine common pathways in the tissue and cell datasets, respectively. Three up-and 10 down-regulated crossing pathways were detected with combined gene set enrichment analysis and meta-analysis. We found that genes with small changes are difficult to detect by classic univariate statistics; they can more easily be identified by pathway analysis. After standardized microarray preprocessing, we applied gene set enrichment analysis and a meta-analysis to increase the concordance in identifying biological mechanisms involved in prostate cancer. The gene pathways that we identified could provide insight concerning the development of prostate cancer.

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“…The use of valproic acid, a histone deacetylate inhibitor (HDACI), also heightened the cytotoxicity of (-)-gossypol. Mechanistically, valproic acid enhanced the induction of mitochondrial stress, as shown by upregulation of glycolysis- and hypoxia-associated proteins ( Ouyang et al, 2011 ). (-)-Gossypol also acted as a radiosensitizer in a study of Xu et al (2005) .…”

Section: Bh3 Mimetics For the Treatment Of Prostate Cancermentioning

confidence: 99%

BH3 Mimetics for the Treatment of Prostate Cancer

Wolf

2017

Front. Pharmacol.

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Despite improved diagnostic and therapeutic intervention, advanced prostate cancer (PC) remains incurable. The acquired resistance of PC cells to current treatment protocols has been traced to apoptosis resistance based on the upregulation of anti-apoptotic proteins of the Bcl-2 family. The use of BH3 mimetics, mimicking pro-apoptotic activator or sensitizer proteins of the intrinsic apoptotic pathway, is therefore a promising treatment strategy. The present review gives an overview of preclinical and clinical studies with pan- and specific BH3 mimetics as sensitizers for cell death and gives an outlook how they could be effectively used for the therapy of advanced PC in future.

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Valproic acid synergistically enhances the cytotoxicity of gossypol in DU145 prostate cancer cells: An iTRTAQ-based quantitative proteomic analysis

Cited by 17 publications

References 57 publications

Transforming growth factor β1 inhibits bone morphogenic protein (BMP)-2 and BMP-7 signaling via upregulation of Ski-related novel protein N (SnoN): possible mechanism for the failure of BMP therapy?

Transforming growth factor β1 inhibits bone morphogenic protein (BMP)-2 and BMP-7 signaling via upregulation of Ski-related novel protein N (SnoN): possible mechanism for the failure of BMP therapy?

Key pathways involved in prostate cancer based on gene set enrichment analysis and meta analysis

BH3 Mimetics for the Treatment of Prostate Cancer

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