Resveratrol Induces Notch2-Mediated Apoptosis and Suppression of Neuroendocrine Markers in Medullary Thyroid Cancer

Truong, Matthew; Cook, Mackenzie R.; Pinchot, Scott N.; Kunnimalaiyaan, Muthusamy; Chen, Herbert

doi:10.1245/s10434-010-1488-z

Cited by 50 publications

(34 citation statements)

References 28 publications

(45 reference statements)

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“…Resveratrol affects Notch signaling at the transcriptional and post-transcriptional levels (affecting the proteolytic cleavagedependent nuclear translocation and activation). It has been shown that resveratrol induces Notch-2 mRNA expression and promotes profound growth inhibition and apoptosis in medullary thyroid cancer cells (17) and human GI carcinoid BON cells (8). It has also been shown that resveratrol represses Notch-1 activation in human T-cell acute lymphoblastic leukemia MOLT-4 cells (19).…”

Section: Discussionmentioning

confidence: 99%

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Lin

Xiong²,

Zhang

et al. 2011

Oncol Rep

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Abstract. Glioblastoma is the most malignant form of adult brain tumor and is associated with a dismal prognosis. Emerging data suggest that Notch signaling participates principally in the formation and malignant progression of glioblastoma. Resveratrol is a terpenoid that exhibits broad pro-apoptotic activity in various types of cancers, including glioblastoma. However, the effects of resveratrol on Notch signaling in glioblastomas have not yet been fully elucidated. We demonstrated that resveratrol strongly suppressed cell growth and induced apoptosis in A172 and T98G glioblastoma cells, which have low active Notch-1 expression and a heterozygous p53 mutation. Our results suggest that resveratrol significantly activates intracellular Notch-1 and restores wild-type p53 expression in a time-dependent manner. Significant de-phosphorylation of Akt, increased Bax expression, decreased Bcl-2 expression and cleavage of caspase-3 were also observed in resveratrol-induced apoptosis in glioblastoma cells. Moreover, simultaneous treatment with resveratrol and a Notch-1 inhibitor (MRK-003) partially attenuated the apoptosis and completely blocked the activation of Notch-1 and the increase in wild-type p53. This suggests that restoration of wild-type p53 expression depends on Notch-1 activation. In addition, the de-phosphorylation of Akt, increased expression of Bax and cleavage of caspase-3 were not fully reversed by MRK-003 treatment, suggesting that p53 restoration is not the only mechanism underlying resveratrol-induced apoptosis. Taken together, we confirmed the anti-proliferative and pro-apoptotic effects of resveratrol on glioblastoma cells and revealed Notch-1 activation-dependent restoration of p53 as an important causative mechanism.

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Section: Discussionmentioning

confidence: 99%

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Lin

Xiong²,

Zhang

et al. 2011

Oncol Rep

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“…Indeed, it has been shown that resveratrol can trigger NOTCH2-dependent apoptosis. 38 Among differentially regulated proteins, we identified BAX, which is able to lead to mitochondria membrane permeabilization, 39 to be phosphorylated on S72, presumably by CK2, in response to resveratrol but not spermidine. Moreover, the stress-responsive apoptosis signaling activator PAK2 was phosphorylated on S141 in response to spermidine but not resveratrol.…”

Section: Phosphorylation Dephosphorylationmentioning

confidence: 92%

Phosphoproteomic analysis of cells treated with longevity-related autophagy inducers

et al. 2012

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“…Resveratrol, a polyphenolic compound found in grapes, red wine, purple grape juice, peanuts, and some berries, induces apoptosis in part by inhibiting Notch and PI3K/AKT in T-ALL cells (Cecchinato et al, 2007) and in glioblastoma cells (Lin et al, 2011). Recently, it has been reported that resveratrol can also activate Notch2 as a mechanism of apoptosis induction in medullary thyroid cancer (Truong et al, 2011) and in carcinoid (Pinchot et al, 2011). Notch2 may function as a Notch1 antagonist due to its lower transcriptional activity.…”

Section: Strategies To Target the Notch Signaling Pathwaymentioning

confidence: 99%

Notch inhibitors for cancer treatment

Espinoza¹,

Miele²

2013

Pharmacology & Therapeutics

243

226

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Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been developed. Most of these inhibitors had shown anti-tumor effects in preclinical studies. At the same time, the combinatorial effect of these inhibitors with current chemotherapeutical drugs still under study in different clinical trials. In this review, we describe the basics of Notch signaling and the role of Notch in normal and cancer stem cells as a logic way to develop different Notch inhibitors and their current stage of progress for cancer patient’s treatment.

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Resveratrol Induces Notch2-Mediated Apoptosis and Suppression of Neuroendocrine Markers in Medullary Thyroid Cancer

Cited by 50 publications

References 28 publications

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells

Phosphoproteomic analysis of cells treated with longevity-related autophagy inducers

Notch inhibitors for cancer treatment

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