PP2A mediates diosmin p53 activation to block HA22T cell proliferation and tumor growth in xenografted nude mice through PI3K–Akt–MDM2 signaling suppression

• Published in: Food and chemical toxicology Vol. 50; no. 5; pp. 1802 - 1810
• Main Authors: Dung, Tran Duc, Day, Cecilia Hsuan, Binh, Truong Viet, Lin, Chih-Hsueh, Hsu, Hsi-Hsien, Su, Cheng-Chuan, Lin, Yueh-Min, Tsai, Fuu-Jen, Kuo, Wei-Wen, Chen, Li-Mien, Huang, Chih-Yang
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-05-2012; Elsevier
• Subjects: Animals; Base Sequence; Biological and medical sciences; Blotting, Western; carcinoma; cell cycle; Cell Cycle - drug effects; cell growth; Cell Line; Cell proliferation; Cell Proliferation - drug effects; cell viability; Diosmin; Diosmin - pharmacology; dose response; Flow Cytometry; Gastroenterology. Liver. Pancreas. Abdomen; Hepatocellular carcinoma; Hepatocytes - drug effects; hepatoma; humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Nude; neoplasm cells; Nude mice model; Okadaic Acid - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; prognosis; Protein Phosphatase 2; Protein phosphatase 2A; proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-mdm2 - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction; small interfering RNA; tissue repair; Toxicology; transfection; Transplantation, Heterologous; Tumor Suppressor Protein p53 - metabolism; Tumors; Western blotting; Cell proliferation; Hepatocellular carcinoma; Nude mice model; Diosmin; Protein phosphatase 2A; Animal model; Phosphoprotein phosphatase; Suppression; Biological model; Phosphoric monoester hydrolases; Hepatic disease; Esterases; Heterograft; Heterotransplantation; Flavonoid; Grafting; mdm2 Gene; Organic pigment; Liver cancer; Signal transduction; Polyphenol; TP53 Gene; EC 3.1.3.16; Protooncogene; Organic compounds; Tumor suppressor gene; Vegetative propagation; Enzyme; Transferases; Rodentia; Akt protein kinase; Malignant tumor; 1-Phosphatidylinositol 3-kinase; Vertebrata; Mammalia; Tumor growth; Mouse; Animal; C-Onc gene; Phenols; Hydrolases; Digestive diseases; Venotropic agent; Cancer
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2012.01.021

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► Diosmin inhibits cell proliferation through PP2A activation in HA22T cells in vitro. ► Diosmin caused no cytotoxicity in normal Chang liver cells. ► Diosmin dramatically suppressed tumor cell proliferation in nude mice model.
Hepatocellular carcinoma is a common type of cancer with poor prognosis. This study examines the in vitro and in vivo mechanisms of diosmin on human hepato-cellular carcinoma HA22T cell proliferation inhibition. HA22T cells were treated with different diosmin concentrations and analyzed with Western blot analysis, MTT assay, wound healing, flow cytometry, siRNA transfection assays and co-immuno-precipitation assay. The HA22T-implanted xeno-graft nude mice model was applied to confirm the cellular effects. Diosmin showed strong HA22T cell viability inhibition in a dose dependent manner and significantly reduced the cell proliferative proteins as well as inducing cell cycle arrest in the G2/M phase through p53 activation and PI3K–Akt–MDM2 signaling pathway inhibition. However, protein phosphatase 2A (PP2A) siRNA or PP2A inhibitor totally reversed the diosmin effects. The HA22T-implanted nude mice model further confirmed that diosmin inhibited HA22T tumor cell growth and down regulated the PI3K–Akt–MDM2 signaling and cell cycle regulating proteins, as well as activating PP2A and p53 proteins. Our findings indicate that HA22T cell proliferation inhibition and tumor growth suppression by diosmin are mediated through PP2A activation.