Resveratrol inhibits cell cycle progression by targeting Aurora kinase A and Polo-like kinase 1 in breast cancer cells
- Authors:
- Published online on: April 4, 2016 https://doi.org/10.3892/or.2016.4728
- Pages: 3696-3704
Abstract
Introduction
Cancer development results from the interaction between genetic factors, environment and dietary factors (1). Breast cancer accounts for 522,000 deaths and is the most frequently diagnosed cancer among women, with 1.7 million cases worldwide in 2012 (2). Even though new strategies for breast cancer therapy are being developed, unfortunately cancer frequently recurs in patients after first-line treatment. Tumor progression is commonly associated with disorders in the regulation of the cell cycle. The Aurora kinase A (AURKA) and Polo-like kinases 1 (PLK1) proteins play key roles in cell cycle phase transition as they co-regulate multiple processes such as mitotic spindle formation, sister chromatid resolution, chromosome spindle connections and cytokinesis. Moreover, AURKA and breast cancer 1 susceptibility (BRCA1) proteins may interplay to control the cell cycle, chromosome polyploidy, and tumorigenesis. The silencing of AURKA was found to suppress cell cycle progression mainly by blocking G1-S and G2-M transition, while the disruption of BRCA1 was found to promote cell cycle progression through induction of G1-S and G2-M transition (3). On the other hand, targeted inhibition of PLK1 can produce antitumor effects, while its constitutive expression in mammalian cells leads to malignant transformation suggesting that aberrant PLK1 expression is oncogenic (4). Because of its important role in cancer, diverse pharmacologic inhibitors have been developed for AURKA (MLN8054, ENMD-2076, Hesperidin and VX680) and PLK1 (BI2536, GSK-461364, Poloxin, CYC-800 and HMN-241) proteins (5). However, resistance to these developed inhibitory molecules is frequently observed in clinical practice; thus alternative therapeutic approaches are needed to overcome resistance and improve patient survival and outcome.
The use of phytochemicals from vegetables, fruits, spices, teas, herbs and medicinal plants, represents one of the most feasible means of cancer chemoprevention (6). Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a phytoalexin found in grapes, berries, peanuts, chocolate, red wine, herbs and plants, and its concentration increases during environmental stress and pathogen invasion. Notably, this natural polyphenol possesses cancer chemopreventive and chemotherapeutic activites by inhibiting diverse cellular events associated with tumor development (7). In fact, resveratrol represents a promising class of anticancer drug, since it acts by targeting multiple proteins in cancer cells having limited toxic effects on normal cells. It also has a potential antitumor effect against the progression of various types of cancer such as prostate, breast, liver, skin and lung cancer (8). Resveratrol exhibits antitumor activity in breast cancer through suppression of migration, invasion and cell cycle progression. It also activates apoptosis leading to chemosensitization of tumor cells in vitro (9). Importantly, resveratrol triggers numerous intracellular pathways leading to cell growth and cell cycle arrest (10). In this study, we evaluated the changes in gene expression profiles induced by resveratrol treatment of MDA-MB-231 breast cancer cells to identify modulated genes that may represent potential therapeutic targets. Interestingly, we found that resveratrol regulates cell cycle progression by targeting AURKA, PLK1 and BRCA1. Our data highlight the potential use of resveratrol in combination with antineoplastic drugs as adjuvant therapy in breast cancer.
Materials and methods
Cell cultures
MCF-7 and MDA-MB-231 breast cancer cell lines were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA). Cells were maintained in Dulbecco's modified Eagle's minimal essential medium (DMEM), supplemented with 10% fetal bovine serum and antibiotics (100 U/ml penicillin and 100 U/ml streptomycin) at 37°C in a humidified atmosphere of 5% CO2.
Reagents
Resveratrol was purchased from Sigma-Aldrich (St. Louis, MO, USA), and dissolved at a concentration of 80 mmol/l in ethanol, stored at −20°C and diluted with DMEM to a 100-µM working concentration.
DNA microarrays and validation
Total RNA was processed and hybridized into the GeneChip Human Gene 1.0 ST (Affymetrix Inc., Santa Clara, CA, USA), following the manufacturer's recommendations. Microarray quality assessment, condensing of the probe sets, data normalization, and filtering were conducted using the Transcriptome Analysis Console version 2.0 (Affymetrix). To identify those biological processes that show differentially expressed genes, we used KEGG and the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.7 for functional annotation. To validate the microarray data, real-time quantitative PCR (RT-qPCR) was performed for 13 selected genes using specific primers (Table I). The SYBR-Green reaction was carried out using a QuantiTect SYBR Green PCR reagents kit (Qiagen) following the manufacturer's recommendations. GADPH expression was used as control. Samples were tested in triplicate and data were analyzed using the 2−∆∆Ct method (11).
Cell cycle analysis
MDA-MB-231 and MCF-7 cells were plated at a density of 5×104 cells/ml for 24 h, and then treated with resveratrol (100 µM) for 24 and 48 h. Cells were harvested by trypsinization and fixed in ice-cold 70% methanol overnight at −20°C. Cells were centrifuged at 1,200 rpm for 5 min and incubated with a propidium iodide (PI) working solution (100 µg/ml PI and 100 µg/ml RNase A) for 30 min at 37°C. Cell cycle distribution was analyzed using a FACScan flow cytometer (FACSCalibur; Becton-Dickinson).
Western blotting
Protein extracts (50 µg) were separated by 12% SDS-PAGE and electrotransferred to a nitrocellulose membrane (Bio-Rad). Membranes were blocked with 5% nonfat milk in PBS with 0.1% Tween-20 and then probed with primary antibodies as follows: anti-AURKA (1:1,000; Cell Signaling Technology), anti-PLK1 (1:500), anti-cyclin D1 (1:1,000), anti-cyclin B1 (1:1,000) and anti-BRCA1 (1:1,000) (all from Santa Cruz Biotechnology), followed by secondary antibodies, anti-rabbit (1:2,500) or anti-mouse (1:2,500) (both from Santa Cruz Biotechnology). The membranes were probed with anti-α-tubulin (1:1,000; Sigma-Aldrich) or actin (1:1,000; Abcam) as a loading control. Immunoreactive bands were developed using the ECL chemiluminescence system (Amersham Pharmacia Biotech).
Statistical analysis
A two-way ANOVA was performed to identify differentially expressed genes of the microarray data. Only genes with statistically significant differences in expression levels (P-value <0.05) and a fold change criteria of ≥1.5 were included in the final set of differentially expressed genes. RT-qPCR results were analyzed using the Student's test. Differences of P<0.05 were considered statistically significant. Values are presented as the mean ± standard deviation of three independent experiments.
Results
Resveratrol induces changes in the transcriptome of human MDA-MB-231 breast cancer cells
Resveratrol is able to inhibit cell viability through apoptosis activation in diverse types of cancer cells (12,13). Here, the effects of resveratrol (100 µM) on cell viability and apoptosis of triple-negative MDA-MB-231 breast cancer cells were evaluated. Results of the MTT, Annexin V and TUNEL assays confirmed that resveratrol treatment was able to significantly (P<0.05) inhibit cell viability and induce apoptosis after 24 and 48 h treatments (data not shown). These results concur with previous reports on diverse types of cancer cells (14–17). Then, in order to obtain insight concerning the cellular transcripts modulated by resveratrol that may explain its anticancer effects, we performed a genome-wide analysis of the transcriptome of MDA-MB-231 breast cancer cells after treatment with resveratrol (100 µM) for 24 and 48 h using DNA microarrays. Data from two biological replicates were analyzed, normalized, and raw P-values adjusted. Only genes with a significant fold change (FC>1.5; P<0.05) were included in this analysis. Transcriptional profiling showed that 375 genes (206 upregulated and 169 downregulated) were significantly modulated at 24 h (Table II). After a 48-h treatment with resveratrol, changes in the expression of 579 genes were detected (338 upregulated and 241 downregulated). Of these, 290 genes (30%) were modulated in common at 24 and 48 h (Fig. 1A).
Overview of the modulated genes by resveratrol in MDA-MB-231 breast cancer cells
To evaluate the impact of resveratrol on cellular processes and pathways of MDA-MB-231 cells, a bioinformatic analysis of the DNA microarray data set was performed. We used the Database for Annotation, Visualization and Integrated Discovery (DAVID) and Reactome Database for functional annotation and visualization of the expression data in the KEGG biological pathway context. Gene ontology category analysis indicated that a number of genes involved in cancer-related processes were modulated by resveratrol at both times (Fig. 1B). Of these, 47 suppressed genes are well-known oncogenes, which highlight the potential effects of resveratrol on the suppression of cancer-related processes. Notably, a significant decrease in the expression of genes involved in the cell cycle, DNA metabolic processes, cytoskeleton organization, metabolism of xenobiotics by cytochrome P450, and angiogenesis was detected at 24 h after resveratrol treatment (Table II). Several of these genes, including SLC6A6, HK2, GPR110, IGHG1, ALOX5AP, CCNB1, CYP1B1, JUN, VEGFA, ANGPTL4 and histones, are clinical therapeutic targets in several types of cancers (18–20). Remarkably, after a 24-h resveratrol treatment we identified the overexpression of a set of DNA repair genes including BRIP1, UNG, BRCA2, MLH1, FANCL, BRCA1, EXO1, CLSPN, BLM, ESCO2, DNA2, POLN (Table II).
In contrast, at 48 h after resveratrol treatment we detected the upregulation of genes involved in cellular response to stress, regulation of cell death, glycolytic process, chromatin organization and cellular senescence. Notably, DNA repair genes involved in homologous recombinational repair (RAD54L, EXO1, RECQL, BRCA1, BRCA2, BLM, DNA2, RBBP8, POLN), mismatch repair (MLH1, MSH2), Fanconi anemia pathway (FANCB, FANCD2, FANCL), base excision repair (UNG), DNA double-strand break repair (BRIP1, FAM175A) and repair of DNA inter-strand crosslinks (EME1) were upregulated at 48 h (Table III). Moreover, several genes involved in cell death, such as TP53I3, CCNE1 and SESN3, were overexpressed at 48 h. Remarkably, 22 and 63 genes involved in the regulation of cell cycle progression were modulated at 24 and 48 h, respectively (Tables II and III). Repressed cell cycle genes at 24 h included AURKA, PLK1, TXNIP, CCNB1, FAM83D, CDCA8, HJURP, CENPA, DLGAP5, BUB1, ASPM, and WEE1; whereas at 48 h of treatment, AURKA, PLK1, JUN, ARHGAP18, KIF20A, SH3KBP, EDN1 and PSMD11 were suppressed. To validate the DNA microarray data, we analyzed using RT-qPCR the expression of 13 modulated genes by resveratrol including six oncogenes at 24 and 48 h. In all cases, the RT-qPCR data were similar to those obtained by the DNA microarray analyses (Fig. 2).
Resveratrol inhibits the G1/S phase transition in breast cancer cells
In our genome-wide analysis of gene expression in MDA-MB-231 cells treated with resveratrol at 24 and 48 h, we identified 63 modulated genes involved in the cell cycle (Tables II and III). Thus, we decided to confirm the effects of resveratrol (100 µM) on cell cycle progression in the MDA-MB-231 and MCF-7 breast cancer cell lines. The cells were treated with resveratrol and the distribution of cell cycle phases was determined by flow cytometric analysis as described in Materials and methods. The results showed that the percentage of cells in the G0–G1 phase increased from 56.7 to 77.3% at 24 h after resveratrol treatment, but retained a normal level at 48 h (54.7%) in comparison to the control (ethanol vehicle) in the MDA-MB-231 cells. This change was accompanied by an increment in the proportion of cells in the S phase from 26.4 in the control to 45.3% in the resveratrol-treated cells at 48 h, but not at 24 h (Fig. 3A). However, we did not observed arrest in the G2-M phase in cells treated with resveratrol at 24 and 48 h, in comparison with the control assays using nocodazole a known blocker of G2-M phase transition. In contrast, in the MCF-7 cells the percentage of cells in the G0–G1 phase did not significantly change after 24 h of resveratrol treatment in comparison with the control, whereas at 48 h we observed a slight but significant increase in cells in the G0–G1 phase (Fig. 3B). Taken altogether, these data indicate that resveratrol inhibits cell cycle progression and that its effects are cell line-specific.
Resveratrol targets the cell cycle regulators AURKA, PLK1, and BRCA1
Our DNA microarrays and RT-qPCR analysis indicated that the activators of cell cycle AURKA, CCND1 and CCNB1 were significantly repressed by resveratrol at 24 and 48 h, whereas PLK1 was only suppressed at 24 h. Moreover, the cell cycle repressor and AURKA/PLK1 inhibitor, BRCA1, was overexpressed at 24 and 48 h after resveratrol treatment. Thus, in order to confirm whether the alterations in mRNA abundance of these cell cycle genes also occur at the protein level, western blot assays using specific antibodies were performed. Results of the immunoblot analysis indicated that changes in the protein levels of these cell cycle genes were correlated with changes at the mRNA level. Data showed that after 24 h of resveratrol treatment, AURKA levels were markedly decreased (95%) in both the MDA-MB-231 and MCF-7 cells in comparison with the control (Fig. 4A and B). In contrast, no significant changes were detected at 48 h in both cell lines. In addition, PLK1 was slightly but significantly decreased by resveratrol at 24 and 48 h in the MDA-MB-231 cells, but not in the MCF-7 cells (Fig. 4C and D). On the other hand, BRCA1 protein levels increased at 24 h whereas no significant changes were identified after 48 h of resveratrol treatment in the MDA-MB-231 cells (Fig. 4A). In addition, we confirmed the suppression of CCND1 and CCNB1 cyclins, which were previously described as two cell cycle markers modulated by resveratrol in MCF-7 and MDA-MB-231 cells (21).
Discussion
Here, we identified novel targets of resveratrol that may represent potential therapeutic targets in breast cancer. Our data showed that, after 24 and 48 h of resveratrol treatment, key genes involved in the regulation of cell cycle progression and DNA repair processes were modulated. These data are relevant as the development of breast cancer is frequently associated with disorders in the regulation of the cell cycle, and enhanced DNA repair is linked to chemotherapy resistance of tumor cells. Failure of the quality control checkpoints or a loss of balance of regulatory molecules plays a major role in carcinogenesis. Of the many regulatory cell cycle checkpoints, the acquisition of abnormalities at the G1/S checkpoint appears to be the most crucial step in the genesis and progression of cancer. Here, we found that resveratrol inhibited the proliferation of MDA-MB-231 and MCF-7 cells by blocking G0–G1 phase transition at 24 h. In agreement with our data, several reports indicate that resveratrol activates apoptosis and inhibits cell proliferation of tumor cells (22,23). Remarkably, we identified two novel targets of resveratrol, the AURKA and PLK1 kinases, which represent pivotal proteins related to cell division. Previous studies indicate that overexpression of AURKA and PLK1 promote cell proliferation through activation of G1/S cell cycle transition in multiple types of carcinomas (24). AURKA belongs to a small family of serine/treonine kinases with evolutionarily conserved structure and participates in mitosis. AURKA is upregulated in a wide range of malignancies and it acts as an oncogene both in vitro and in vivo, by enhancing G1-S transition, protecting cells from apoptosis, inducing centrosome amplification, promoting multipolar spindle formation and genomic instability, and conferring resistance to antitumor agents. PLK1 is a checkpoint protein that participates in the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the mitotic exit and cytokinesis. As PLK1 activates cyclin B and stimulates cell proliferation, its silencing results in an inactivation of cyclin B/Cdc2 complex-mediated mitotic arrest followed by apoptosis (25). As these kinases may co-regulate several processes in mitosis, some overlap in the clinical performance of drugs that target PLK1 or aurora kinases is possible. However, the knowledge of the molecular factors that influence sensitivity and resistance to AURKA and PLK1 inhibitors remains limited.
On the other hand, we found that resveratrol (100 µM) treatment resulted in the upregulation of the BRCA1 gene in MDA-MB-231 cells at 24 and 48 h. Similar results were reported in breast cancer cell lines at low resveratrol doses (30 µM) in previous research (26). BRCA1 is a tumor suppressor that plays critical roles in DNA repair, cell cycle checkpoint control, and maintenance of genomic stability. It also suppresses the cell cycle progression. Remarkably, a molecular interplay between AURKA, PLK1 and BRCA1 proteins has been reported. BRCA1 inhibits the kinase activity of PLK1 by modulating the interactions of AURKA with hBora, and PLK1 (27). Our data confirm that resveratrol suppresses the expression of both CCND1 (G1-S transition) and CCNB1 (G2-M transition) cyclins at 24 h and 48 h in MDA-MB-231 and MCF-7 cells. Similar results for CCND1 and CCNB1 were previously described in SW-480 colorectal cancer cells and MCF-7 breast cancer cells (28). Taken all together, we propose a working model for cell cycle regulation by resveratrol in MDA-MB-231 cells (Fig. 5). In conclusion, the present study shows for the first time that resveratrol reduced mRNA and protein expression levels of AURKA and PLK1 two potential therapeutic targets in cancer. Our findings revealed the role of resveratrol in important cellular processes and in the modulation of key cell cycle regulators, which highlights its potential use as an adjuvant in breast cancer therapy.
Abbreviations:
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AURKA |
Aurora protein kinase |
|
PLK1 |
Polo-like kinase-1 |
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CCND1 |
cyclin D1 |
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CCNB1 |
cyclin B1 |
Acknowledgments
CONACyT SALUD grants (233370 and 222335) supported this work. R.M. was supported by a CONACYT doctoral fellowship.
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