title: Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator.
abstract: The antitumor activities of the novel adenosine monophosphate-activated protein kinase (AMPK) activator, OSU-53, were assessed in in vitro and in vivo models of triple-negative breast cancer. OSU-53 directly stimulated recombinant AMPK kinase activity (EC(50), 0.3 μM) and inhibited the viability and clonogenic growth of MDA-MB-231 and MDA-MB-468 cells with equal potency (IC(50), 5 and 2 μM, respectively) despite lack of LKB1 expression in MDA-MB-231 cells. Nonmalignant MCF-10A cells, however, were unaffected. Beyond AMPK-mediated effects on mammalian target of rapamycin signaling and lipogenesis, OSU-53 also targeted multiple AMPK downstream pathways. Among these, the protein phosphatase 2A-dependent dephosphorylation of Akt is noteworthy because it circumvents the feedback activation of Akt that results from mammalian target of rapamycin inhibition. OSU-53 also modulated energy homeostasis by suppressing fatty acid biosynthesis and shifting the metabolism to oxidation by up-regulating the expression of key regulators of mitochondrial biogenesis, such as a peroxisome proliferator-activated receptor γ coactivator 1α and the transcription factor nuclear respiratory factor 1. Moreover, OSU-53 suppressed LPS-induced IL-6 production, thereby blocking subsequent Stat3 activation, and inhibited hypoxia-induced epithelial-mesenchymal transition in association with the silencing of hypoxia-inducible factor 1a and the E-cadherin repressor Snail. In MDA-MB-231 tumor-bearing mice, daily oral administration of OSU-53 (50 and 100 mg/kg) suppressed tumor growth by 47-49% and modulated relevant intratumoral biomarkers of drug activity. However, OSU-53 also induced protective autophagy that attenuated its antiproliferative potency. Accordingly, cotreatment with the autophagy inhibitor chloroquine increased the in vivo tumor-suppressive activity of OSU-53. OSU-53 is a potent, orally bioavailable AMPK activator that acts through a broad spectrum of antitumor activities.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, Ohio 43210-1291, USA.
authors.forename: Kuen-Haur
authors.initials: KH
authors.lastname: Lee
authors.forename: En-Chi
authors.initials: EC
authors.lastname: Hsu
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.forename: Hsiao-Ching
authors.initials: HC
authors.lastname: Yang
authors.forename: Dasheng
authors.initials: D
authors.lastname: Wang
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D020536:Enzyme Activators / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D005227:Fatty Acids; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; C000599963:OSU-53; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D045162:Thiazolidinediones; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2