BACKGROUND: Perifosine, an alkylphospholipid, is an Akt inhibitor which inhibits the growth of diverse cancer cells. We have reported its inhibitory effects on the growth of gastric cancer cells recently, but its molecular mechanisms are still largely unknown. AIMS: The purpose of this study was to investigate the effect and regulatory mechanism of perifosine in gastric cancer. METHODS: Cell viability was determined by sulforhodamine B assay after transiently transfected with AEG-1 specific siRNAs. qRT-PCR and western blot assay were used to determine the mRNA expression and proteins levels of cell signaling molecules examined. Immunohistochemistry was used to detect the AEG-1 expression in 87 gastric carcinomas, 60 dysplasia, and 47 normal gastric mucosa. RESULTS: Perifosine decreased AEG-1 gene expression along with inhibition of Akt/GSK3β/C-MYC signaling pathway. Knockdown of AEG-1 using siRNA led to significant down-regulation of cyclin D1 expression at both mRNA level and protein level, and inhibited the growth of gastric cancer cells. AEG-1 expression was elevated in gastric dysplasia and cancer tissues compared to normal gastric mucosa (P < 0.01). AEG-1 over-expression correlated with diffuse type of gastric cancer and advanced tumor stages. CONCLUSIONS: Perifosine inhibits the growth of gastric cancer cells possibly through inhibition of the Akt/GSK3β/C-MYC signaling pathway-mediated down-regulation of AEG-1 that subsequently down-regulated cyclin D1. AEG-1 may play an important role in the carcinogenesis and progression of gastric cancer and could be a therapeutic target of perifosine.
BACKGROUND:Perifosine, an alkylphospholipid, is an Akt inhibitor which inhibits the growth of diverse cancer cells. We have reported its inhibitory effects on the growth of gastric cancer cells recently, but its molecular mechanisms are still largely unknown. AIMS: The purpose of this study was to investigate the effect and regulatory mechanism of perifosine in gastric cancer. METHODS: Cell viability was determined by sulforhodamine B assay after transiently transfected with AEG-1 specific siRNAs. qRT-PCR and western blot assay were used to determine the mRNA expression and proteins levels of cell signaling molecules examined. Immunohistochemistry was used to detect the AEG-1 expression in 87 gastric carcinomas, 60 dysplasia, and 47 normal gastric mucosa. RESULTS:Perifosine decreased AEG-1 gene expression along with inhibition of Akt/GSK3β/C-MYC signaling pathway. Knockdown of AEG-1 using siRNA led to significant down-regulation of cyclin D1 expression at both mRNA level and protein level, and inhibited the growth of gastric cancer cells. AEG-1 expression was elevated in gastric dysplasia and cancer tissues compared to normal gastric mucosa (P < 0.01). AEG-1 over-expression correlated with diffuse type of gastric cancer and advanced tumor stages. CONCLUSIONS:Perifosine inhibits the growth of gastric cancer cells possibly through inhibition of the Akt/GSK3β/C-MYC signaling pathway-mediated down-regulation of AEG-1 that subsequently down-regulated cyclin D1. AEG-1 may play an important role in the carcinogenesis and progression of gastric cancer and could be a therapeutic target of perifosine.
Authors: Pier Luigi Tazzari; Giovanna Tabellini; Francesca Ricci; Veronica Papa; Roberta Bortul; Francesca Chiarini; Camilla Evangelisti; Giovanni Martinelli; Andrea Bontadini; Lucio Cocco; James A McCubrey; Alberto M Martelli Journal: Cancer Res Date: 2008-11-15 Impact factor: 12.701
Authors: Anna Dubrovska; Sungeun Kim; Richard J Salamone; John R Walker; Sauveur-Michel Maira; Carlos García-Echeverría; Peter G Schultz; Venkateshwar A Reddy Journal: Proc Natl Acad Sci U S A Date: 2008-12-30 Impact factor: 11.205
Authors: Sudhir B Kondapaka; Sheo S Singh; Girija P Dasmahapatra; Edward A Sausville; Krishnendu K Roy Journal: Mol Cancer Ther Date: 2003-11 Impact factor: 6.261