Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator

Kuen Haur Lee, En Chi Hsu, Jih Hwa Guh, Hsiao Ching Yang, Dasheng Wang, Samuel K. Kulp, Charles L. Shapiro, Ching Shih Chen

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)39247-39258
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number45
DOIs
Publication statusPublished - Nov 11 2011
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Adenosine Monophosphate
Protein Kinases
Tumors
Autophagy
Sirolimus
Nuclear Respiratory Factor 1
Bearings (structural)
Chemical activation
OSU-53
Protein Phosphatase 2
Neoplasms
Lipogenesis
Peroxisome Proliferator-Activated Receptors
Epithelial-Mesenchymal Transition
Biosynthesis
Chloroquine
Biomarkers
Organelle Biogenesis
Cadherins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. / Lee, Kuen Haur; Hsu, En Chi; Guh, Jih Hwa; Yang, Hsiao Ching; Wang, Dasheng; Kulp, Samuel K.; Shapiro, Charles L.; Chen, Ching Shih.

In: Journal of Biological Chemistry, Vol. 286, No. 45, 11.11.2011, p. 39247-39258.

Research output: Contribution to journalArticle

Lee, Kuen Haur ; Hsu, En Chi ; Guh, Jih Hwa ; Yang, Hsiao Ching ; Wang, Dasheng ; Kulp, Samuel K. ; Shapiro, Charles L. ; Chen, Ching Shih. / Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 45. pp. 39247-39258.
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