Morin fosters apoptosis in experimental hepatocellular carcinogenesis model.
Here we investigated the in vivo effect of morin (500ppm in diet) in fostering apoptosis in diethylnitrosamine (DEN) (200mg/kg bodyweight) mediated experimental hepatocellular carcinogenesis model. We analyzed the expression of cytosolic protein Akt and their important apoptotic downstream targets like caspase-9, Bcl-2, Bax, GSK-3betain vivo, by immunoblot analysis. In silico docking studies indicated that morin could serve as a better inhibitor than the classical PI3K inhibitor LY294002. The results obtained from in vivo studies confirm this. We also demonstrate here that morin's interaction with a defined set of amino acids of PI3K p110gamma catalytic subunit resulted in the down-regulation of p-Akt(Ser473), p-Akt(Thr308) and total Akt causing the attenuation of its downstream targets in DEN-induced hepatocellular carcinoma. Further, morin caused the up-regulation of tumor suppressor PTEN, an important negative regulator of Akt, thus initiating apoptosis. Supplementation of morin to experimental animals modulated Bcl-2/Bax ratio causing the release of cyt C and up-regulation of caspase-3 and -9. Morin was also found to prevent the Akt-mediated suppression of GSK-3beta possibly causing cell cycle arrest at the G1/S phase. These observations were supported by the DNA fragmentation and transmission electron microscopy results, which showed the occurrence of apoptosis. In conclusion, our findings demonstrate that morin begets apoptosis in DEN-induced hepatocellular carcinoma.
Sivaramakrishnan
Venkatabalasubramanian
V
Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamilnadu, India.
Devaraj
Sivasitambaram Niranjali
SN
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003198:Computer Simulation; D004052:Diethylnitrosamine / Q000633:toxicity; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D016193:G1 Phase; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016196:S Phase; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D047309:Flavones
D000970:Antineoplastic Agents; D000975:Antioxidants; D053148:Caspase 3; D053453:Caspase 9; D004052:Diethylnitrosamine; D005419:Flavonoids; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051028:bcl-2-Associated X Protein; C008548:morin; D047309:Flavones; C000605507:Gsk3b protein, mouse; C487757:Pten protein, mouse