Valproic Acid Activates Notch-1 Signaling and Regulates the Neuroendocrine Phenotype in Carcinoid Cancer Cells

Greenblatt, David Yü; Vaccaro, Abram; Jaskula-Sztul, Renata; Li, Ning; Haymart, Megan R.; Kunnimalaiyaan, Muthusamy; Chen, Herbert

doi:10.1634/theoncologist.12-8-942

Cited by 125 publications

(157 citation statements)

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“…In a recent study valproic acid (a NOTCH activator) treatment of gastrointestinal and pulmonary neuroendocrine tumor cell lines resulted in a dose-dependent inhibition of cancer cell growth and also increased levels of full-length NOTCH1 and the active NOTCH1 intracellular domain 9. 22 This study underscores the need for a site-based critical assessment of signaling pathways, when designing clinical trials for gastrointestinal neuroendocrine tumors.…”

Section: Discussionmentioning

confidence: 84%

Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway

et al. 2013

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The molecular pathogenesis of gastroenteropancreatic neuroendocrine tumors is largely unknown. We hypothesize that gastroenteropancreatic neuroendocrine tumors are heterogeneous with regard to these signaling pathways and these differences could have a significant impact on the outcome of clinical trials. We selected 120 well-differentiated neuroendocrine tumors including tumors originating in pancreas (n ¼ 74), ileum (n ¼ 31), and rectum (n ¼ 15). Immunohistochemistry was performed on tissue microarrays using the following antibodies: NOTCH1, HES1, HEY1, pIGF1R, and FGF2. Gene profiling study was performed by using human genome U133A 2.0 array and data were analyzed. The gene profiling results were selectively confirmed by using quantitative reverse-transcription PCR. Initial immunohistochemical analysis showed NOTCH1 was uniformly expressed in rectal neuroendocrine tumors (100%), a subset of pancreatic neuroendocrine tumors (34%), and negative in ileal neuroendocrine tumors. Similarly, a downstream target of NOTCH1, HES1 was preferentially expressed in rectal neuroendocrine tumors (64%), a subset of pancreatic neuroendocrine tumors (10%), and uniformly negative in ileal neuroendocrine tumors. Messenger RNAs for NOTCH1, HES1, and HEY1 were 2.32-, 2.44-, and 2.39-folds, respectively, higher in rectal neuroendocrine tumors as compared with ileal neuroendocrine tumors. Global gene expression profiling showed 95 genes were differentially expressed in small intestinal vs rectal neuroendocrine tumors, with changes as high as 50-fold. These genes were concentrated in several signal transduction pathways including cancer endocrine pathway and cell growth/proliferation pathway. The differential expression of selected genes including ISL LIM homeobox 1, cathepsin B, glucagon, and tryptophan hydroxylase 1 were confirmed by qPCR and immunohistochemistry. Our results confirm the heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors. NOTCH1 inhibitors are unlikely to provide benefit in ileal neuroendocrine tumors; conversely, their efficacy in rectal neuroendocrine tumors needs further study. Further analysis of signaling pathways is critical for designing clinical trials in gastroenteropancreatic neuroendocrine tumors.

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Section: Discussionmentioning

confidence: 84%

Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway

et al. 2013

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“…Given that VPA has been reported to activate Notch1 signaling in several NET cell lines (13,20), we were interested in determining the ability of VPA to activate Notch1 signaling in SCLC cells. To assess this, we measured protein levels of full-length Notch1 and NICD after treatment with various concentrations of VPA.…”

Section: Vpa Induces Notch1 Signaling In Sclc Cellsmentioning

confidence: 99%

“…We have previously shown that Notch1 signaling is minimal or absent at baseline in several NET cell lines, and that expression of exogenous Notch1 via an inducible construct inhibits NET cell growth (6,14). Additionally, VPA has been reported to activate Notch1 signaling in neuroblastoma, carcinoid, and medullary thyroid cancer cells (13,19,20). We hypothesized, then, that VPA may also activate Notch1 signaling in SCLC cells with subsequent anti-tumor effects.…”

Section: Introductionmentioning

confidence: 98%

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Valproic Acid Induces Notch1 Signaling in Small Cell Lung Cancer Cells

Platta

Greenblatt

Kunnimalaiyaan

et al. 2008

Journal of Surgical Research

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Background-Small cell lung cancer (SCLC) is an aggressive malignancy. Current treatments yield dismal survival rates. We have previously demonstrated that histone deacetylase (HDAC) inhibitors can inhibit neuroendocrine tumor growth. Activation of the Notch1 signaling pathway also impairs SCLC cell viability. In this study, we investigated the ability of the HDAC inhibitor valproic acid (VPA) to activate Notch1 signaling and inhibit proliferation in SCLC cells.

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“…Some researches revealed up-regulation of Bak protein expression, degradation of cyclin D1 and an increase in cyclin-dependent kinases p21 and p27 after sodium valproate treatment. In addition, sodium valproate also increased the levels of full-length Notch-1 and active Notch-1 intracellular domain, which intern inhibit proliferation and induced apoptosis of neoplasm (Greenblatt et al, 2007;Fortunati et al, 2008;Platta et al, 2008). Sami et al in cervical cancer found that sodium valproate can increase the expression of histone H3 acetylation and up-regulate p21 expression (Sami et al, 2008).…”

Section: 6429 Effects Of Sodium Valproate On the Growth Of Human Ovamentioning

confidence: 97%

Effects of Sodium Valproate on the Growth of Human Ovarian Cancer Cell Line HO8910

Yan

Zhang²

2012

Asian Pacific Journal of Cancer Prevention

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To explore a possible new treatment for human ovarian cancer, we studied the effects of sodium valproate on the growth of the HO8910 human cell line. HO8910 cells were cultured in vitro and treated with different concentrations of sodium valproate. Cell proliferation, cell cycling, and apoptosis were measured by flow cytometry, cell morphology under a microscope, and expression levels of WWOX and P27 by Western blotting and RT-PCR. Tumor xenografts were established to determine in vivo effects of sodium valproate. Our results showed that cell proliferation was decreased with increasing concentration of sodium valproate, with features of cytoplasmic retraction and floating cells. Moreover, cell cycle analysis revealed a higher apoptosis rate and G 0 / G 1 phase in the sodium valproate experimental group than in the control group. In addition, protein expression levels of WWOX and P27 were elevated. Importantly, sodium valproate decreased in vivo xenograft tumor burden and up-regulated WWOX and P27 expression in nude mice. In conclusion, sodium valproate might play a role in inhibition and control of ovarian cancer cell line HO8910 by inhibiting cell proliferation, interfering with the cell cycle and promoting apoptosis, so that it may be effective in the clinical treatment of ovarian cancer. Keywords: Ovarian cancer -apoptosis -WWOX -P27 -sodium valproate RESEARCH ARTICLE Effects of Sodium Valproate on the Growth of Human Ovarian Cancer Cell Line HO8910Hong-Chao Yan*, Jie Zhang an experimental cell model and the effects of sodium valproate has been investigated on its proliferation, cell cycle, and apoptosis. Materials and Methods Cell CultureHO8910 ovarian cancer cell line, obtained from the Gynecology Department Laboratory of our hospital, Xuzhou, China, were cultured in RPMI 1640 (Hangzhou Sijiqing Biology Engineering Materials Co., Ltd. China) medium supplemented with 10% fetal bovine serum (Hangzhou Sijiqing Biology Engineering Materials Co., Ltd. China), penicillin and streptomycin, in a humidified atmosphere containing 5% CO 2 at 37°C. Experimental groupingThe HO8910 cells were randomly divided into a control group and experiment groups. The experiment groups were cultured in the medium with 1.0, 2.0, 3.0 and 4.0 mmol/L concentrations of sodium valproate (Sigma aldrich, USA), while normal culture medium had been used in the control group. Methylthiazol tetrazolium (MTT) Cell Proliferation AssayMTT cell proliferation assay kit (Beyotime, China) was used for this assay. Briefly, HO8910 cells were trypsinized

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Valproic Acid Activates Notch-1 Signaling and Regulates the Neuroendocrine Phenotype in Carcinoid Cancer Cells

Cited by 125 publications

References 45 publications

Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway

Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway

Valproic Acid Induces Notch1 Signaling in Small Cell Lung Cancer Cells

Effects of Sodium Valproate on the Growth of Human Ovarian Cancer Cell Line HO8910

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