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

Abstract

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.

Resveratrol Induces Differentiation Markers Expression in Anaplastic Thyroid Carcinoma via Activation of Notch1 Signaling and Suppresses Cell Growth

“…In our study, it was found that resveratrol activated Notch1 signaling in the ATC context. Consistent with two other studies (36,37), this indicates that the Notch1 pathway could be another important signaling cascade involved in resveratrol-induced cell growth inhibition. In one of our previous studies, genetic induction of Notch1in the thyroid cancer xenografts profoundly suppressed tumor growth (38).…”

Notch inhibitors for cancer treatment

“…Curcumin downregulates Notch1 and induces apoptosis through inactivation of NF-κB in pancreatic cancer cells (Wang et al, 2006b) and in oral cancer cells (Liao et al, 2011). 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).…”

How to Take Autophagy and Endocytosis Up a Notch

“…In addition, resveratrol was found in a high-throughput screen for the identification of Notch activating compounds using carcinoid cell lines [102], and treatment of thyroid carcinoma cells with resveratrol was shown to inhibit growth by arresting cell-cycle progression in the S-phase and induce Notch protein expression and signaling by transcriptional regulation [103, 104]. Furthermore, resveratrol also suppressed cellular growth and activated Notch expression in glioblastoma [105]. In contrast to most other studies, a microarray analysis to search for genes expressed in adipose tissue of obese men treated with resveratrol found genes of the Notch signaling pathway to be downregulated, whereas autophagy genes were found to be upregulated [106].…”