Luteolin suppresses cancer cell proliferation by targeting vaccinia-related kinase 1

• Published in: PloS one Vol. 9; no. 10; p. e109655
• Main Authors: Kim, Ye Seul, Kim, Seong-Hoon, Shin, Joon, Harikishore, Amaravadhi, Lim, Jong-Kwan, Jung, Youngseob, Lyu, Ha-Na, Baek, Nam-In, Choi, Kwan Yong, Yoon, Ho Sup, Kim, Kyong-Tai
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.10.2014; Public Library of Science (PLoS)
• Subjects: Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; B cells; Biology and Life Sciences; Biotechnology; Cancer; Cancer therapies; Catalysis; Catalytic Domain - drug effects; Cell cycle; Cell division; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cyclic AMP response element-binding protein; Deoxyribonucleic acid; DNA; DNA damage; DNA-Binding Proteins - metabolism; Drug delivery; Drugs; Flavonoids; Health aspects; Histone H3; Histones - metabolism; Humans; Inhibitors; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - chemistry; Kinases; Life sciences; Luteolin - chemistry; Luteolin - pharmacology; Metastasis; Nuclear Proteins - metabolism; Phase transitions; Phosphatase; Phosphorylation; Phosphorylation - drug effects; Phosphotransferases; Polyphenols; Protein binding; Protein kinase; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Proteins; Regulators; Side effects; Substrates; Therapy; Vaccinia; South Korea; Singapore
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0109655

Uncontrolled proliferation, a major feature of cancer cells, is often triggered by the malfunction of cell cycle regulators such as protein kinases. Recently, cell cycle-related protein kinases have become attractive targets for anti-cancer therapy, because they play fundamental roles in cellular proliferation. However, the protein kinase-targeted drugs that have been developed so far do not show impressive clinical results and also display severe side effects; therefore, there is undoubtedly a need to investigate new drugs targeting other protein kinases that are critical in cell cycle progression. Vaccinia-related kinase 1 (VRK1) is a mitotic kinase that functions in cell cycle regulation by phosphorylating cell cycle-related substrates such as barrier-to-autointegration factor (BAF), histone H3, and the cAMP response element (CRE)-binding protein (CREB). In our study, we identified luteolin as the inhibitor of VRK1 by screening a small-molecule natural compound library. Here, we evaluated the efficacy of luteolin as a VRK1-targeted inhibitor for developing an effective anti-cancer strategy. We confirmed that luteolin significantly reduces VRK1-mediated phosphorylation of the cell cycle-related substrates BAF and histone H3, and directly interacts with the catalytic domain of VRK1. In addition, luteolin regulates cell cycle progression by modulating VRK1 activity, leading to the suppression of cancer cell proliferation and the induction of apoptosis. Therefore, our study suggests that luteolin-induced VRK1 inhibition may contribute to establish a novel cell cycle-targeted strategy for anti-cancer therapy.