AMPK-sensed cellular energy state regulates the release of extracellular Fatty Acid Synthase

Fatty Acid Synthase (FASN), a 250-kDa cytosolic multi-enzyme catalyzing eukaryotic de novo FA biogenesis, unexpectedly localizes in cancer cell culture supernatants and in the blood of cancer patients. High levels of “extracellular FASN” have recently been found in supernatants from Hepatitis C Viru...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2009-01, Vol.378 (3), p.488-493
Main Authors: Oliveras-Ferraros, Cristina, Vazquez-Martin, Alejandro, Fernández-Real, Jose Manuel, Menendez, Javier A.
Format: Article
Language:English
Subjects:
Adenosine Monophosphate - metabolism
Adenosine Triphosphate - metabolism
AICAR
Aminoimidazole Carboxamide - analogs & derivatives
Aminoimidazole Carboxamide - pharmacology
AMP-Activated Protein Kinases - antagonists & inhibitors
AMP-Activated Protein Kinases - genetics
AMP-Activated Protein Kinases - metabolism
AMPK
Antibodies, Monoclonal - immunology
Cancer
Cell Line, Tumor
Culture Media, Conditioned
Cytosol - enzymology
Diabetes
Energy Metabolism
Fatty Acid Synthase
Fatty Acid Synthase, Type I - antagonists & inhibitors
Fatty Acid Synthase, Type I - immunology
Fatty Acid Synthase, Type I - metabolism
Hepatitis C
Humans
Isoenzymes - antagonists & inhibitors
Isoenzymes - immunology
Isoenzymes - metabolism
Neoplasms - enzymology
Obesity
Ribonucleotides - pharmacology
RNA, Small Interfering - genetics
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Summary:Fatty Acid Synthase (FASN), a 250-kDa cytosolic multi-enzyme catalyzing eukaryotic de novo FA biogenesis, unexpectedly localizes in cancer cell culture supernatants and in the blood of cancer patients. High levels of “extracellular FASN” have recently been found in supernatants from Hepatitis C Virus-infected liver cells. The ultimate mechanism regulating FASN release, however, remained completely undefined. When the AMPK-activating drug AICAR was used to simulate an elevated AMP/ATP ratio in breast cancer cells, ELISA-based analyses revealed that extracellular FASN dramatically augmented in a dose- and time-dependent manner. Immunoblotting procedures using a battery of anti-FASN antibodies further confirmed that, in response to AMPK activation, FASN protein is depleted from the cytosol to accumulate as different FASN isoforms in the extracellular milieu. siRNA-induced blockade of AMPK expression largely attenuated AICAR-promoted FASN release. FASN release might represent a previously unrecognized mechanism through which AMPK monitor and restores cellular energy state in response to increasing AMP/ATP ratios.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2008.11.067