Original Article
Citation: Cell Death and Disease (2015) 6, e1714; doi:10.1038/cddis.2015.86
Published online 9 April 2015
Published online 9 April 2015
Oroxylin A inhibits glycolysis-dependent proliferation of
human breast cancer via promoting SIRT3-mediated SOD2 transcription and
HIF1α destabilization
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- 1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
- 2JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
Correspondence:
Q Guo or N Lu or Q You, State Key Laboratory of Natural Medicines,
Jiangsu Key Laboratory of Carcinogenesis and Intervention, China
Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People’s
Republic of China, Tel: +86 25 83271055; Fax: +86 25 83271055; E-mail: anticancer_drug@163.com or luna555@163.com or youqd@163.com
3These authors contributed equally to this work.
Received 29 September 2014; Revised 22 February 2015; Accepted 23 February 2015
Edited by C Munoz-Pinedo
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Abstract
Alterations
of cellular metabolism play a central role in the development and
progression of cancer. Oroxylin A, an active flavonoid of a Chinese
traditional medicinal plant, was previously shown to modulate glycolysis
in cancer cells. However, the mechanism by which oroxylin A regulates
glycolysis is still not well defined. Here, we show that oroxylin A
inhibits glycolysis in breast cancer cells via the Sirtuin 3
(SIRT3)-mediated destabilization of hypoxia-inducible factor 1α (HIF1α),
which controls glycolytic gene expression. Oroxylin A promotes
superoxide dismutase (SOD2) gene expression through SIRT3-regulated
DNA-binding activity of FOXO3a and increases the activity of SOD2 by
promoting SIRT3-mediated deacetylation. In vivo, oroxylin A
inhibits the growth of transplanted human breast tumors associated with
glycolytic suppression. These data indicate that oroxylin A inhibits
glycolysis-dependent proliferation of breast cancer cells, through the
suppression of HIF1α stabilization via SIRT3 activation, providing preclinical information for the cancer therapies of SIRT3 stimulation.
Abbreviations:
SIRT3, sirtuin 3; SOD2, superoxide dismutase; HIF1α, hypoxia-inducible factor 1α;
GLUT, glucose transporter 1; HKII, hexokinase II; PDK1, pyruvate
dehydrogenase kinase 1; ROS, reactive oxygen species; PHDs, prolyl
hydroxylases; FOXO3a, forkhead box O3a; DMOG, dimethyloxaloylglycine;
TSA, trichostatin A; NAM, nicotinamide; ADM, Adriamycin; mtDNA,
mitochondrial DNA; Ac-SOD2, acetylated-SOD2
