Resveratrol inhibits cell cycle progression by targeting Aurora kinase A and Polo-like kinase 1 in breast cancer cells.
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.
Department of Genetics and Molecular Biology, CINVESTAV-IPN, Mexico D.F., Mexico.
Rubiceli
R
Medina-Aguilar
Molecular Biomedicine Program and Biotechnology Network, National School of Medicine and Homeopathy, National Polytechnic Institute, Mexico D.F., Mexico.
Laurence A
LA
Marchat
Natural Sciences Department, Metropolitan Autonomous University, Mexico D.F., Mexico.
Elena
E
Arechaga Ocampo
Department of Genetics and Molecular Biology, CINVESTAV-IPN, Mexico D.F., Mexico.
Patricio
P
Gariglio
Department of Genetics and Molecular Biology, CINVESTAV-IPN, Mexico D.F., Mexico.
Jaime
J
García Mena
Department of Molecular Biomedicine, CINVESTAV‑IPN, Mexico D.F., Mexico.
Nicolás
N
Villegas Sepúlveda
Department of Molecular Biomedicine, CINVESTAV‑IPN, Mexico D.F., Mexico.
Macario
M
Martínez Castillo
Oncogenomics and Cancer Proteomics Laboratory, Universidad Autónoma de la Ciudad de México, Mexico D.F., Mexico.
César
C
López-Camarillo
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D056744:Cyclin B1 / Q000037:antagonists & inhibitors; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D059467:Transcriptome / Q000235:genetics; D000097869:Polo-Like Kinase 1
D000972:Antineoplastic Agents, Phytogenic; D064096:Aurora Kinase A; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000077185:Resveratrol; D013267:Stilbenes; D000097869:Polo-Like Kinase 1; C492913:BRCA1 protein, human; C534699:CCNB1 protein, human; C530104:CCND1 protein, human; C576917:AURKA protein, human