Inhibition of Fatty-acid Synthase Induces Caspase-8-mediated Tumor Cell Apoptosis by Up-regulating DDIT4
作者： Lynn M. Knowles , Chen Yang , Andrei Osterman , Jeffrey W. Smith
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摘要: Fatty-acid synthase (FAS) is up-regulated in a broad range of cancers, including those the breast, prostate, and ovaries. In tumor cells, inhibition FAS elicits cell cycle arrest apoptosis, so it considered potential drug target for oncology. Results from this study show that FAS, by either knockdown with small interfering RNA or molecule orlistat, leads to activation receptor-mediated apoptotic cascade (caspase-8-mediated) ultimately death. However, two enzymes upstream acetyl-CoA carboxylase-α ATP-citrate lyase, fails activate caspase-8 elicit apoptosis even though palmitate synthesis was suppressed. Using differential gene analysis, we traced unique effect up-regulation DDIT4 (DNA damage-inducible transcript 4), stress-response negatively regulates mTOR pathway. These findings indicate suppression not sufficient eliciting death suggest results negative regulation pathway via DDIT4.
medicinabiomolecular.com.br 参考文章(54)
Jean-Luc Bodmer, Nils Holler, Séverine Reynard, Patrizia Vinciguerra, Pascal Schneider, Peter Juo, Joe Blenis, Jürg Tschopp, TRAIL receptor-2 signals apoptosis through FADD and caspase-8 Nature Cell Biology. ,vol. 2, pp. 241- 243 ,(2000) , 10.1038/35008667
Daniela Siegmund, Philipp Hadwiger, Klaus Pfizenmaier, Hans-Peter Vornlocher, Harald Wajant, Selective Inhibition of FLICE-like Inhibitory Protein (FLIP) Expression With Small Interfering RNA Oligonucleotides (siRNAs) Is Sufficient to Sensitize Tumor Cells for TRAIL-Induced Apoptosis Molecular Medicine. ,vol. 8, pp. 725- 732 ,(2002) , 10.1007/BF03402036
Koen Brusselmans, Ellen De Schrijver, Johannes V. Swinnen, Walter Heyns, Guido Verhoeven, RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells. Cancer Research. ,vol. 63, pp. 3799- 3804 ,(2003)
Francis P. Kuhajda, Ellen S. Pizer, Fawn D. Wood, Gary R. Pasternack, Fatty acid synthase (FAS)) : a target for cytotoxic antimetabolites in HL60 promyelocytic leukemia cells Cancer Research. ,vol. 56, pp. 745- 751 ,(1996)
Francis P. Kuhajda, Ellen S. Pizer, Gary R. Pasternack, Marianna Zahurak, Stanley R. Hamilton, Asif Rashid, Lea Z. Milgraum, Michael Moga, Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. American Journal of Pathology. ,vol. 150, pp. 201- 208 ,(1997)
Francis P. Kuhajda, Ellen S. Pizer, Henry S. Heine, Fawn D. Wood, Gary R. Pasternack, Fedor E. Romantsev, Inhibition of Fatty Acid Synthesis Delays Disease Progression in a Xenograft Model of Ovarian Cancer Cancer Research. ,vol. 56, pp. 1189- 1193 ,(1996)
Miranda Kleijn, Gert C. Scheper, Harry O. Voorma, Adri A. M. Thomas, Regulation of translation initiation factors by signal transduction FEBS Journal. ,vol. 253, pp. 531- 544 ,(1998) , 10.1046/J.1432-1327.1998.2530531.X
Christoph Wittmann, Elmar Heinzle, Mass spectrometry for metabolic flux analysis Biotechnology and Bioengineering. ,vol. 62, pp. 739- 750 ,(1999) , 10.1002/(SICI)1097-0290(19990320)62:6<739::AID-BIT13>3.0.CO;2-E
Piero L. Alo, Paolo Visca, Adele Marci, Antonella Mangoni, Claudio Botti, Ugo Di Tondo, Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients Cancer. ,vol. 77, pp. 474- 482 ,(1996) , 10.1002/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO;2-K
Jagan N. Thupari, Michael L. Pinn, Francis P. Kuhajda, Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. Biochemical and Biophysical Research Communications. ,vol. 285, pp. 217- 223 ,(2001) , 10.1006/BBRC.2001.5146