Resveratrol inhibits cell cycle progression by targeting Aurora kinase A and Polo-like kinase 1 in breast cancer cells

Abstract

The Aurora protein kinase (AURKA) and the Polo-like kinase-1 (PLK1) activate the cell cycle, and they are considered promising druggable targets in cancer therapy. However, resistance to chemotherapy and to specific small‑molecule inhibitors is common in cancer patients; thus alternative therapeutic approaches are needed to overcome clinical resistance. Here, we showed that the dietary compound resveratrol suppressed the cell cycle by targeting AURKA and PLK1 kinases. First, we identified genes modulated by resveratrol using a genome-wide analysis of gene expression in MDA-MB-231 breast cancer cells. Transcriptional profiling indicated that 375 genes were modulated at 24 h after resveratrol intervention, whereas 579 genes were regulated at 48 h. Of these, 290 genes were deregulated in common at 24 and 48 h. Interestingly, a significant decrease in the expression of genes involved in the cell cycle, DNA repair, cytoskeleton organization, and angiogenesis was detected. In particular, AURKA and PLK1 kinases were downregulated by resveratrol at 24 h. In addition the BRCA1 gene, an AURKA/PLK1 inhibitor, was upregulated at 24 h of treatment. Moreover, two well-known resveratrol effectors, cyclin D1 (CCND1) and cyclin B1 (CCNB1), were also repressed at both times. Congruently, we found that resveratrol impaired G1/S phase transition in both MDA-MB-231 and MCF-7 cells. By western blot assays, we confirmed that resveratrol suppressed AURKA, CCND1 and CCNB1 at 24 and 48 h. In summary, we showed for the first time that resveratrol regulates cell cycle progression by targeting AURKA and PLK1. Our findings highlight the potential use of resveratrol as an adjuvant therapy for breast cancer.

Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21CIP1 in human breast cancer cell lines

“…Resveratrol (RVT) a natural polyphenolic compound found in grapes and berries has been widely studied and is considered as an anti‐cancer, anti‐diabetes, cardioprotective, and anti‐inflammatory molecule . Its molecular targets include AKT, mTOR, NF‐kB, STAT, MAPK, AURKA, and PLK1, resulting in their inactivation and subsequent inhibition of cell proliferation . In another hand, RVT was shown to induce cell cycle arrest by activation of p53, p27, p21, and p16 .…”

“…14 Its molecular targets include AKT, mTOR, NF-kB, STAT, MAPK, AURKA, and PLK1, resulting in their inactivation and subsequent inhibition of cell proliferation. 15,16 In another hand, RVT was shown to induce cell cycle arrest by activation of p53, p27, p21, and p16. [17][18][19] A plethora of studies have shown RVT affect multiple epigenetic events, including DNA methyltransferases or DNMTs, sirtuin HDACs (SIRT1 and SIRT2), and lysine-specific demethylase 1.…”

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization

“…MCF7/T46D and MDA-MB-231 cells were seeded at a density of 5000 cells/well in a 96-well plate and incubated overnight. Seeded cells were treated with ISO and Rsv for 48 h. Most of the previous studies reported the highest anti-cancer efficacy of Rsv following 48 h of treatment [49][50][51]. Therefore, we chose this time point to determine the anti-cancer effects of ISO.…”

The paradoxical pro‐ and antiangiogenic actions of resveratrol: therapeutic applications in cancer and diabetes

“…Treatment of mammary cancer in rats with high doses of resveratrol reduced cellular proliferation, increased apoptosis, and decreased angiogenesis in mammary epithelial cells via AKT inactivation and modulation of forkhead transcription factors, resulting in tumor suppression . A significant decrease in the expression of genes involved in the cell cycle, DNA repair, cytoskeleton organization, and angiogenesis after resveratrol treatment have been attributed to the downregulation of cell cycle activators, such as Aurora protein kinase (AURKA) and the Polo‐like kinase‐1 (PLK1) . Furthermore, resveratrol has been shown to play a role in upregulation of death‐associated protein kinase 2 (DAPK2) and BCL2/adenovirus E1B 19‐kDa interacting protein 3 (BNIP3), as well as downregulation of fatty acid synthetase (FAS), in tumor microenvironments …”

“…100 A significant decrease in the expression of genes involved in the cell cycle, DNA repair, cytoskeleton organization, and angiogenesis after resveratrol treatment have been attributed to the downregulation of cell cycle activators, such as Aurora protein kinase (AURKA) and the Polo-like kinase-1 (PLK1). 101 Furthermore, resveratrol has been shown to play a role in upregulation of death-associated protein kinase 2 (DAPK2) and BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), as well as downregulation of fatty acid synthetase (FAS), in tumor microenvironments. 102 Prostate.…”