Valproic acid inhibits the invasion of PC3 prostate cancer cells by upregulating the metastasis suppressor protein NDRG1

Lee, Jae Eun; Kim, Jung Hwa

doi:10.1590/s1415-475738420150028

Cited by 29 publications

(18 citation statements)

References 29 publications

(42 reference statements)

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“…It has been reported that HDACIs are able to induce tumor cell death with similar physiological and morphological characteristics to those of apoptosis, particularly as they are selective and exert minimal toxic effects on the host ( 19 ). In a previous study, it was demonstrated that VPA significantly decreased the proliferation of prostate cancer cells in vitro and reduced tumor volume ( 20 ). It was considered that this antitumor activity may be associated with temporary cell arrest and downregulated expression of androgen receptors induced by chronic VPA treatment ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

et al. 2016

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Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

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Section: Discussionmentioning

confidence: 99%

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

et al. 2016

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“…Undoubtedly, agents that can efficiently inhibit the growth and migration of cancer cells are candidates to suppress cancer progression and metastasis and thus are likely to reduce mortality. Previous reports have demonstrated that the anticancer activity of VPA is more effective on metastatic prostate cancer cells than non-metastatic cells [ 37 ]. In this study, we examined the effects of combined treatment with VPA and 5-Aza on the migratory capacity of 786-O and 769-P cells.…”

Section: Discussionmentioning

confidence: 99%

Combined Treatment with Valproic Acid and 5-Aza-2’-Deoxycytidine Synergistically Inhibits Human Clear Cell Renal Cell Carcinoma Growth and Migration

Sun

et al. 2018

Med Sci Monit

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BackgroundHistone acetylation and DNA methylation are important mammalian epigenetic modifications that participate in the regulation of gene expression. Because dysregulation of histone deacetylase and DNA methyltransferases are hallmarks of malignancy, they have become promising therapeutic targets. In this study, we explored the anti-tumor activity of valproic acid (VPA), a histone deacetylase inhibitor (HDACi) and 5-Aza-2′-deoxycytidine (5-Aza), an inhibitor of DNA methyltransferases, on renal cell carcinoma (RCC) cell lines 786-O and 769-P.Material/MethodsThe cell proliferation was detected by xCELLigence RTCA DP Instrument, viability by CCK8 assay, cell apoptosis and cell cycle by flow cytometry, and cell migration by wound healing assay, Transwell assay and xCELLigence RTCA DP Instrument.ResultsWe discovered that VPA and 5-Aza could individually induce decreased viability and have an inhibitory effect on the proliferation of 786-O and 769-P cells. This anti-growth effect was more pronounced when the cells were treated with both VPA and 5-Aza. The combination of VPA and 5-Aza also elicited more apoptosis and produced more cell cycle arrest in the G1 phase for both cell lines. On the other hand, treatment of RCC cells with VPA, 5-Aza, or a combination of both resulted in slow wound healing and impaired migration.ConclusionsThese findings clearly demonstrated that VPA combined with 5-Aza could significantly increase anti-RCC effects by inhibiting cellular proliferation, inducing apoptosis, promoting cell cycle arrest and prohibiting the migration of human RCC cells.

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“…Valproic acid (VPA) also reduced cell viability and induced apoptosis in vitro and was able to reduce tumor growth in xenograft models [ 192 ]. Moreover, this compound inhibited epithelial-mesenchymal transition (EMT) and invasion abilities of PC-3 cells by decreasing SMAD4 protein expression and upregulating the metastasis suppressor gene N-myc downstream regulated gene-1 ( NDRG1 ), respectively [ 193 , 194 ]. In a TRAMP model of PCa treated with VPA, decreased tumor growth and invasiveness correlated with the re-expression of CCND2 , a frequently silenced gene in PCa [ 195 ].…”

Section: Epigenetic Silencing As a Therapeutic Target In Prostate Canmentioning

confidence: 99%

Epigenetic modulators as therapeutic targets in prostate cancer

et al. 2016

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Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.

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Valproic acid inhibits the invasion of PC3 prostate cancer cells by upregulating the metastasis suppressor protein NDRG1

Cited by 29 publications

References 29 publications

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

Combined Treatment with Valproic Acid and 5-Aza-2’-Deoxycytidine Synergistically Inhibits Human Clear Cell Renal Cell Carcinoma Growth and Migration

Epigenetic modulators as therapeutic targets in prostate cancer

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