Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator
Journal
Journal of Biological Chemistry
Journal Volume
286
Journal Issue
45
Pages
39247-39258
Date Issued
2011
Author(s)
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. ? 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
SDGs
Other Subjects
Anti-proliferative; Anti-tumor activities; Autophagy; Breast Cancer; Broad spectrum; Coactivators; Dephosphorylations; E-cadherins; Energy homeostasis; Fatty acid biosynthesis; Hypoxia-inducible factors; In-vitro; In-vivo; Key regulators; Kinase activity; Lipogenesis; Mammalian target; Mitochondrial biogenesis; Nuclear respiratory factors; Oral administration; Peroxisome proliferator-activated receptor; Protein kinase; Protein phosphatase 2A; Signaling pathways; Tumor growth; Antibiotics; Biochemistry; Biosynthesis; Cytology; Diseases; Enzymes; Fatty acids; Immunology; Mammals; Metabolism; Physiology; Signaling; Transcription factors; Tumors; Chemical activation; adenosine monophosphate activated protein kinase; adenosine phosphate; antineoplastic agent; chloroquine; hypoxia inducible factor 1alpha; interleukin 6; mammalian target of rapamycin; nuclear respiratory factor 1; osu 53; peroxisome proliferator activated receptor gamma coactivator 1alpha; phosphoprotein phosphatase 2A; protein kinase B; STAT3 protein; transcription factor Snail; unclassified drug; uvomorulin; animal cell; animal experiment; animal model; antineoplastic activity; article; cancer inhibition; carcinogenicity; controlled study; cytokine production; drug bioavailability; drug determination; drug structure; energy metabolism; enzyme activation; enzyme activity; epithelial mesenchymal transition; fatty acid synthesis; female; in vitro study; in vivo study; lipogenesis; mouse; nonhuman; priority journal; protein dephosphorylation; protein expression; protein targeting; signal transduction; treatment response; triple negative breast cancer; AMP-Activated Protein Kinases; Animals; Breast Neoplasms; Cell Line, Tumor; Energy Metabolism; Enzyme Activators; Fatty Acids; Female; Humans; Interleukin-6; Lipopolysaccharides; Mice; Mice, Nude; Mitochondria; Neoplasm Proteins; Protein Phosphatase 2; Signal Transduction; STAT3 Transcription Factor; Transcription Factors; Gastropoda; Mammalia; Mus
Type
journal article