Resveratrol inhibits glioma cell growth via targeting oncogenic microRNAs and multiple signaling pathways

Abstract

Abstract. Resveratrol (Res), a natural polyphenolic compound, has anticancer activity in a variety of cancers. In the present study, the antitumor effect and underlying molecular mechanism of Res on rat C6 glioma growth was studied. The results demonstrated that Res inhibited glioma cell proliferation, arrested cell cycle in S phase and induced apoptosis in vitro. Res also suppressed intracranial C6 tumor growth in vivo and prolonged survival in a fraction of the rats bearing intracranial gliomas. Res significantltly downregulated the specific miRs, including miR-21, miR-30a-5p and miR-19, which have been identified as oncomiRs in our previous studies, and altered the expression of their targeting and crucial genes for glioma formation and progression such as p53, PTEN, EGFR, STAT3, COX-2, NF-κB and PI3K/AKT/mTOR pathway. Therefore, the anti-glioma effect of Res, at least in part, is through the regulation of oncogenic miRNAs. The effect of Res on noncoding RNAs should be studied further. Res is a potential multi-targeting drug for the treatment of gliomas. IntroductionMalignant gliomas are the most common and highly aggressive primary brain tumors. Even using multiple modalities of treatment, including maximal safe resection, radiotherapy, and chemotherapy, the prognosis of patients with malignant gliomas remains dismal (1,2). Therefore, novel therapeutic strategies and drugs for treatment of malignant gliomas are urgently required.A large number of chemopreventive and chemotherapeutic agents have been discovered from natural products and provided promising approaches to treat and prevent cancer (3,4). Res (3,5,4'-trihydroxy-trans-stilbene), a naturally polyphenolic compound, has been identified in the skin of red grapes, peanuts and various food products. It has a variety of important biological effects such as suppression of platelet aggregation, anti-inflammatory, anti-oxidant, and vasorelaxant activities (5-7). Res also exhibits antitumor properties by blocking the three stages of carcinogenesis, initiation, promotion and progression (8). Res has exerted anticancer effects against prostate, breast, leukemia and other epithelial cancer cells. There are some reports on the studies of the treatment of gliomas with Res (9-12) but the molecular mechanism of its antitumorigenic or chemopreventive activities is complex and not fully understood.The objective of the present study was to investigate the anti-proliferative effect of Res on glioma cells using both in vitro and in vivo models. It is well known that small non-coding regulatory RNAs -microRNAs (miRs) are found to be dysregulated in almost all types of cancers and play important roles in cancer development and progression (13)(14)(15)(16)(17). Recent studies have demonstrated that miRs can be regulated by natural agents such as curcumin and Res resulting in suppression of tumor growth, drug resistance and metastasis (18-21). Our previous studies have confirmed that specific miRs, including miR-21, miR19 and miR-30a-5p are upregulated in GBMs with significa...

Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells

“…Our results indicate that Res shows no substantial effect on the mRNA level of PTEN in HCT116 cells, or the total protein level of PTEN. However, Res can apparently decrease the phosphorylation of PTEN, which is consistent with the previous studies that PTEN is involved in the anticancer effect of Res in cancer cells (45)(46)(47). To further unveil the relationship between BMP7 and PTEN, we introduced the BMP7 recombinant adenovirus and a specific antibody.…”

The emerging role of miR‐19 in glioma

“…p53 has also been identified to be the target gene of miR‐19 in Hela cell 40. In glioma, expression of p53 is correlated negatively with that of miR‐19 31. p53 can impose cell cycle arrest and inhibit cell growth by decreasing the expression of Cyclin E1 and CDK2 41, 42.…”

Attenuation of Oxidative Stress in HEK 293 Cells by the TCM Constituents Schisanhenol, Baicalein, Resveratrol or Crocetin and Two Defined Mixtures

“…Here, we evaluated the chemoprotectant effects of these four major TCM constituents (baicalein (BE), crocetin (Cro), transresveratrol (Res) and schisanhenol (Sal) and two defined mixtures against the well characterized, cellpermeant oxidative and nitrosative stressor, tertiarybutyl hydroperoxide (tBHP) (12,13) in wild-type (WT) transformed human renal epithelial cells (HEK 293) cells and HEK 293 cells bioengineered to express the cholinergic neuron-specific enzyme choline acetyltransferase (ChAT, EC 2.3.1.6) (14,15) (ChAT-HEK 293 cells). Recognizing that TCMs also have cytoprotective effects due to modulation of cell signalling pathways (16)(17)(18)(19), we sought to optimize the opportunity for complementary biological activity in our defined mixtures by selecting four TCM antioxidants of varying structure and chemical class ( Figure 1) with known and diverse mechanisms of antioxidant and cytoprotective activity. Baicalein (BE) [5,6,7-trihydroxy-2-phenylchromen-4-one] ( Figure 1B) (16,(20)(21)(22)(23)(24) is the flavonoid found at highest concentration in the root of Scutellaria baicalensis, a common component of TCM prescriptions.…”