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 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.
Oliveras-Ferraros
Cristina
C
Catalan Institute of Oncology, Girona (ICO-Girona), Hospital de Girona "Dr. Josep Trueta", Ctra. França s/n, E-17007 Girona, Catalonia, Spain.
Vazquez-Martin
Alejandro
A
Fernández-Real
Jose Manuel
JM
Menendez
Javier A
JA
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D003600:Cytosol / Q000201:enzymology; D004734:Energy Metabolism; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology; D034741:RNA, Small Interfering / Q000235:genetics; D012265:Ribonucleotides / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D007527:Isoenzymes; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide