Two specific inhibitors of the phosphatidylinositol 3-kinase LY294002 and wortmannin up-regulate beta1,4-galactosyltransferase I and thus sensitize SMMC-7721 human hepatocarcinoma cells to cycloheximide-induced apoptosis.
Previous study indicated that beta1,4-galactosyltransferase I (beta1,4GT1) was up-regulated by cycloheximide (CHX) and thus enhanced apoptosis induced by CHX in SMMC-7721 cells. In this study, we reported that constitutively active Akt protein (myr-Akt) inhibited CHX-induced apoptosis in SMMC-7721 cells through down-regulating beta1,4GT1. However, the two PI3K inhibitors LY294002 and wortmannin treatment up-regulated beta1,4GT1 through enhancing Sp1 protein expression and consequently increased CHX-induced SMMC-7721 cells apoptosis. Besides, our results suggested that beta1,4GT1 and cell surface galactose residues synthesized by elevated beta1,4GT1 played an important role in SMMC-7721 cells apoptosis treated with CHX and PI3K inhibitor together. Moreover, we found that CHX accentuated beta1,4GT1 through down-regulating Akt expression to mediate SMMC-7721 cells apoptosis. Taken together, PI3K inhibitors LY294002 and wortmannin up-regulated beta1,4GT1 and enhanced CHX-induced apoptosis in SMMC-7721 cells, which suggested that PI3K inhibitors might have therapeutic potential when combined with CHX in the treatment of hepatoma.
Shen
Jialin
J
Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032, P. R. China.
Jiang
Jianhai
J
Wei
Yuanyan
Y
Zhou
Lei
L
Liu
Dan
D
Zhou
Jin
J
Gu
Jianxin
J
D000730:Androstadienes / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005700:Galactosyltransferases / Q000235:genetics* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009025:Morpholines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D013379:Substrate Specificity; D015854:Up-Regulation / Q000187:drug effects; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003513:Cycloheximide; D005700:Galactosyltransferases; C493310:beta1,4-galactosyltransferase, human; D019869:Phosphatidylinositol 3-Kinases; D000077191:Wortmannin