Cyanidin-3-o-β-Glucoside Induces Megakaryocyte Apoptosis via PI3K/Akt- and MAPKs-Mediated Inhibition of NF-κB Signalling

Fuli Ya; Qing Li; Dongliang Wang; Shuangfeng Xie; Fenglin Song; Reid C. Gallant; Zezhong Tian; Jianbo Wan; Wenhua Ling; Yan Yang

doi:10.1055/s-0038-1656551

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(07): 1215-1229
DOI: 10.1055/s-0038-1656551

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

Cyanidin-3-o-β-Glucoside Induces Megakaryocyte Apoptosis via PI3K/Akt- and MAPKs-Mediated Inhibition of NF-κB Signalling

Authors

Fuli Ya^*

¹Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China

²Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China
Qing Li^*

¹Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China

²Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China
Dongliang Wang

¹Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China

²Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China
Shuangfeng Xie

³Department of Hematology, 2nd Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
Fenglin Song

⁴School of Food Science, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
Reid C. Gallant

⁵Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada

⁶Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada

⁷Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
Zezhong Tian

¹Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China

²Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China
Jianbo Wan

⁸State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
Wenhua Ling

¹Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China

²Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China
Yan Yang

¹Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China

²Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, China

⁹School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong Province, China

Abstract

Apoptotic-like phase is an essential step in thrombopoiesis from megakaryocytes. Anthocyanins are natural flavonoid pigments that possess a wide range of biological activities, including protection against cardiovascular diseases and induction of tumour cell apoptosis. We investigated the effects and underlying mechanisms of cyanidin-3-o-β-glucoside (Cy-3-g, the major bioactive compound in anthocyanins) on the apoptosis of human primary megakaryocytes and Meg-01 cell line in vitro. We found that Cy-3-g dose-dependently increased the dissipation of the mitochondrial membrane potential, caspase-9 and caspase-3 activity in megakaryocytes from patients with newly diagnosed acute myeloid leukaemia but not in those from healthy volunteers. In Meg-01 cells, Cy-3-g regulated the distribution of Bak, Bax and Bcl-xL proteins in the mitochondria and cytosol, subsequently increasing cytochrome c release and stimulating caspase-9 and caspase-3 activation and phosphatidylserine exposure. However, Cy-3-g did not exert significant effects on factor-associated suicide (Fas), Fas ligand, caspase-8 or Bid expression. Cy-3-g inhibited nuclear factor kappa B (NF-κB) p65 activation by down-regulating inhibitor of NF-κB kinase (IKK)α and IKKβ expression, followed by the inhibition of inhibitor of NF-κB (IκB)α phosphorylation and degradation and subsequent inhibition of the translocation of the p65 sub-unit into the nucleus, and finally stimulating caspase-3 activation and phosphatidylserine exposure. The inhibitory effect of Cy-3-g on NF-κB activation was mediated by the activation of extracellular signal-regulated kinases (Erk1/2) and p38 mitogen-activated protein kinase (MAPK) and the inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling. U0126 (Erk1/2 inhibitor), SB203580 (p38 MAPK inhibitor) and 740 Y-P (PI3K agonist) significantly reversed Cy-3-g-reduced phosphorylation of p65. Taken together, our data indicate that Cy-3-g induces megakaryocyte apoptosis via the inhibition of NF-κB signalling, which may play important roles in regulating thrombopoiesis.

Keywords

megakaryocyte - thrombopoiesis - anthocyanins - Cy-3-g - apoptosis

Full Text

References

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