title: Inhibition of ATP citrate lyase induces an anticancer effect via reactive oxygen species: AMPK as a predictive biomarker for therapeutic impact.
abstract: De novo lipogenesis is activated in most cancers. Inhibition of ATP citrate lyase (ACLY), the enzyme that catalyzes the first step of de novo lipogenesis, leads to growth suppression and apoptosis in a subset of human cancer cells. Herein, we found that ACLY depletion increases the level of intracellular reactive oxygen species (ROS), whereas addition of an antioxidant reduced ROS and attenuated the anticancer effect. ACLY depletion or exogenous hydrogen peroxide induces phosphorylation of AMP-activated protein kinase (p-AMPK), a crucial regulator of lipid metabolism, independently of energy status. Analysis of various cancer cell lines revealed that cancer cells with a higher susceptibility to ACLY depletion have lower levels of basal ROS and p-AMPK. Mitochondrial-deficient ρ(0) cells retained high levels of ROS and p-AMPK and were resistant to ACLY depletion, whereas the replenishment of normal mitochondrial DNA reduced the levels of ROS and p-AMPK and restored the sensitivity to ACLY depletion, indicating that low basal levels of mitochondrial ROS are critical for the anticancer effect of ACLY depletion. Finally, p-AMPK levels were significantly correlated to the levels of oxidative DNA damage in colon cancer tissues, suggesting that p-AMPK reflects cellular ROS levels in vitro and in vivo. Together, these data suggest that ACLY inhibition exerts an anticancer effect via increased ROS, and p-AMPK could be a predictive biomarker for its therapeutic outcome.
authors.affiliation: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Migita
authors.forename: Sachiko
authors.initials: S
authors.lastname: Okabe
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Saori
authors.initials: S
authors.lastname: Igarashi
authors.forename: Shoko
authors.initials: S
authors.lastname: Sugawara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomida
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Seimiya
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D001275:ATP Citrate (pro-S)-Lyase; D055372:AMP-Activated Protein Kinases