title: Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells.
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.
authors: Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, PR China.
authors: Hong
authors: H
authors: Lin
authors: Wei
authors: W
authors: Xiong
authors: Xiang
authors: X
authors: Zhang
authors: Bolin
authors: B
authors: Liu
authors: Wei
authors: W
authors: Zhang
authors: Yongqiang
authors: Y
authors: Zhang
authors: Jinxiang
authors: J
authors: Cheng
authors: Huiyong
authors: H
authors: Huang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016158:Genes, p53; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; C497761:NOTCH1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051881:Receptor, Notch1; D013267:Stilbenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol