Apoptosis in human hepatoma cell line induced by 4,5-didehydro geranylgeranoic acid (acyclic retinoid) via down-regulation of transforming growth factor-alpha.
Synthetic 4,5-didehydro GGA (geranylgeranoic acid), a potent ligand both for cellular retinoic acid-binding protein and for nuclear retinoid receptors, induced apoptosis in human hepatoma-derived cell line HuH-7 but not in primary hepatocytes, although all-trans or 9-cis retinoic acid did not induce any growth inhibition. Either exogenous transforming growth factor-alpha (TGF alpha) or epidermal growth factor(EGF) prevented the cells from apoptosis in the presence of 4,5-didehydro GGA, but hepatocyte growth factor, insulin-like growth factor-II, insulin or triiodothyronine was essentially inactive. 4,5-Didehydro GGA down-regulated the cellular levels of TGF alpha mRNA as early as 30 min after the treatment. Either anti-TGF alpha or anti-EGF receptor monoclonal antibody induced apoptosis in HuH-7 cells without using the acid. Taken together, the present study strongly suggests that 4,5-didehydro GGA induced apoptosis in HuH-7 cells through the destruction of autocrine loop consisting of TGF alpha and EGF receptor, due to the down regulation of TGF alpha gene expression.
Nakamura
N
N
First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Shidoji
Y
Y
Moriwaki
H
H
Muto
Y
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis* / Q000494:pharmacology*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D014284:Triiodothyronine; D014212:Tretinoin; D004815:Epidermal Growth Factor; D007335:Insulin-Like Growth Factor II; C034534:3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid; D066246:ErbB Receptors