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Mol Carcinog. 2018 Oct;57(10):1267-1277. doi: 10.1002/mc.22841. Epub 2018 Jun 5.

Nummularic acid, a triterpenoid, from the medicinal plant Fraxinus xanthoxyloides, induces energy crisis to suppress growth of prostate cancer cells.

Author information

1
Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
2
Faculty of Biological Sciences, Department of Biochemistry, Quaid-i-Azam University Islamabad, Islamabad, Pakistan.
3
Faculty of Life Sciences, Department of Zoology, Government College University Faisalabad, Faisalabad, Pakistan.
4
Faculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
5
Faculty of Science, Cancer Metabolism and Epigenetic Unit, King Abdulaziz University, Jeddah, Saudi Arabia.

Abstract

We recently identified and characterized nummularic acid (NA) as a major chemical constituent of Fraxinus xanthoxyloides, a medicinal plant used for over hundred years in traditional medicine. In this study, we describe its potential anti-cancer activity using prostate cancer (PCa) cells as a model. We found that NA treatment (5-60 μM) significantly reduced the proliferation and colony formation capabilities of PCa DU145 and C4-2 cells in a time and dose dependent manner, reduced the migratory and invasive properties and increased apoptotic cell population. Mechanistically, we found that NA treatment to PCa cells resulted in a sustained activation of adenosine monophosphate-activated protein kinase (AMPK). NA simultaneously increased acetyl CoA carboxylase phosphorylation and decreased pS6 phosphorylation, the two major substrates of AMPK. Further, NA treatment significantly elevated the cellular ADP/ATP ratio and altered glycolytic rate. We further observed a reversible decrease in oxygen consumption rate in NA treated cells when compared to the control. Finally, we performed global untargeted metabolomics which showed that NA treatment alters PCa cell metabolism at multiple sites including glycolysis, tricarboxylic acid, and glutamine metabolism which supported our observation of a possible AMPK activation. In summary, we report NA as a novel small molecule activator of AMPK that alters cellular metabolism to induce energy crisis and ultimately cancer cell death. Because of its unique mechanism NA could be potentially applicable against other cancer types.

KEYWORDS:

5′AMP activated kinase; AMPK; metabolism; proliferation

PMID:
29802724
DOI:
10.1002/mc.22841
[Indexed for MEDLINE]

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