Reduced expression of FASN through SREBP-1 down-regulation is responsible for hypoxic cell death in HepG2 cells.
Cells under hypoxic stress either activate an adaptive response or undergo cell death. Although some mechanisms have been reported, the exact mechanism behind hypoxic cell death remains unclear. Recently, increased expression of fatty acid synthase (FASN) has been observed in various human cancers. In highly proliferating cells, tumor-associated FASN is considered necessary for both membrane lipids production and post-translational protein modification, but the exact mechanisms are not fully understood. Further, FASN overexpression is associated with aggressive and malignant cancer diseases and FASN inhibition induces apoptosis in cancer cells. For this reason, FASN is emerging as a key target for the potential diagnosis and treatment of various cancers. Here, we observed decreased FASN expression under hypoxic cell death conditions in HepG2 cells. Thus, we examined the effect of decreased FASN expression on hypoxia-induced cell death in HepG2 cells and also investigated the mechanism responsible for reduction of FASN expression under hypoxic cell death conditions. As a result, reduction of FASN expression resulted in hypoxic cell death via malonyl-CoA accumulation. In addition, SREBP-1 restored FASN reduction and hypoxia-induced apoptosis. Taken together, we suggest that hypoxic cell death is promoted by the reduced expression of FASN through SREBP-1 down-regulation.
Department of Molecular Biology, Pusan National University, Busan 609-735, Korea.
Seung-Youn
SY
Jung
Hye-Kyung
HK
Jeon
Jae-Sun
JS
Choi
Yung-Jin
YJ
Kim
D002452:Cell Count; D016923:Cell Death; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D015536:Down-Regulation; D015180:Electrophoresis, Gel, Two-Dimensional; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D008316:Malonyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D008316:Malonyl Coenzyme A; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D005947:Glucose