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: Kuen-Haur Lee, En-Chi Hsu, Jih-Hwa Guh, Hsiao-Ching Yang, Dasheng Wang, Samuel K Kulp, Charles L Shapiro, Ching-Shih Chen
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 45 Pg. 39247-58 (Nov 11 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21917926 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Activators
• Fatty Acids
• IL6 protein, human
• Interleukin-6
• Lipopolysaccharides
• Neoplasm Proteins
• OSU-53
• STAT3 Transcription Factor
• STAT3 protein, human
• Sulfonamides
• Thiazolidinediones
• Transcription Factors
• peroxisome-proliferator-activated receptor-gamma coactivator-1
• AMP-Activated Protein Kinases
• Protein Phosphatase 2

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Animals
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Energy Metabolism (drug effects, genetics)
• Enzyme Activators (pharmacology)
• Fatty Acids (biosynthesis, genetics)
• Female
• Humans
• Interleukin-6 (biosynthesis, genetics)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Nude
• Mitochondria (enzymology, genetics)
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Protein Phosphatase 2 (genetics, metabolism)
• STAT3 Transcription Factor (biosynthesis, genetics)
• Signal Transduction (drug effects, genetics)
• Sulfonamides (pharmacology)
• Thiazolidinediones (pharmacology)
• Transcription Factors (genetics, metabolism)