Fatty acid synthase inhibition activates AMP-activated protein kinase in SKOV3 human ovarian cancer cells.
Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation.
Zhou
Weibo
W
Departments of Pathology, Neuroscience, Neurology, Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, USA.
Han
Wan Fang
WF
Landree
Leslie E
LE
Thupari
Jagan N
JN
Pinn
Michael L
ML
Bililign
Tsion
T
Kim
Eun Kyoung
EK
Vadlamudi
Aravinda
A
Medghalchi
Susan M
SM
El Meskini
Rajaa
R
Ronnett
Gabriele V
GV
Townsend
Craig A
CA
Kuhajda
Francis P
FP
D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005663:Furans / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005663:Furans; D009097:Multienzyme Complexes; D009243:NAD; C014289:5-(tetradecyloxy)-2-furancarboxylic acid; D064429:Fatty Acid Synthases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose