Coumestrol induces senescence through protein kinase CKII inhibition-mediated reactive oxygen species production in human breast cancer and colon cancer cells

• Published in: Food chemistry Vol. 141; no. 1; pp. 381 - 388
• Main Authors: Lee, Young-Hoon, Yuk, Heung Joo, Park, Ki-Hun, Bae, Young-Seuk
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.11.2013; Elsevier
• Subjects: Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - physiopathology; Cancer cells; Casein Kinase II - antagonists & inhibitors; Casein Kinase II - chemistry; Casein Kinase II - genetics; Casein Kinase II - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular Senescence - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - metabolism; Colonic Neoplasms - physiopathology; Coumestrol; Coumestrol - pharmacology; Down-Regulation - drug effects; Female; Glycine max - chemistry; HCT116 Cells; Humans; Kinetics; Male; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Plant Extracts - pharmacology; Protein kinase CKII; Reactive Oxygen Species - metabolism; ROS; Senescence; Soybean; Tumors; Senescence; Soybean; Coumestrol; ROS; Cancer cells; Protein kinase CKII; Human; Oxidative stress; Reactive oxygen species; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Ageing; Malignant tumor; EC 2.7.1.37; Grain legume; Production; Breast; Colon; Mammary gland; Inhibition; Tumor cell; Cancer
• ISSN: 0308-8146; 1873-7072
• DOI: 10.1016/j.foodchem.2013.03.053

•Coumestrol purified from soybean leaves inhibited protein kinase CKII activity.•Coumestrol induced ROS production through CKII inhibition in cancer cells.•It promoted senescence through the p53-p21Cip1/WAF1 pathway in cancer cells.•CKIIα overexpression suppressed coumestrol-mediated senescence in cancer cells.•This study provides a novel mechanism for tumour inhibition by coumestrol. An inhibitor of the protein kinase CKII (CKII) was purified from leaves of Glycine max (L.) Merrill and was identified as coumestrol by structural analysis. Coumestrol inhibited the phosphotransferase activity of CKII toward β-casein, with an IC50 of about 5μM. It acted as a competitive inhibitor with respect to ATP as a substrate, with an apparent Ki value of 7.67μM. Coumestrol at 50μM resulted in 50% and 30% growth inhibition of human breast cancer MCF-7 and colorectal cancer HCT116 cells, respectively. Coumestrol promoted senescence through the p53-p21Cip1/WAF1 pathway by inducing reactive oxygen species (ROS) production in MCF-7 and HCT116 cells. The ROS scavenger N-acetyl-l-cysteine (NAC), NADPH oxidase inhibitor apocynin and p22phox siRNA almost completely abolished this event. Overexpression of CKIIα antagonised cellular senescence mediated by coumestrol, indicating that this compound induced senescence via a CKII-dependent pathway. Since senescence is an important tumour suppression process in vivo, these results suggest that coumestrol can function by inhibiting oncogenic disease, at least in part, through CKII inhibition-mediated cellular senescence.