Bouchardatine suppresses rectal cancer in mice by disrupting its metabolic pathways via activating the SIRT1-PGC-1α-UCP2 axis

Xu, Y, Song, Q, Li, C, Hu, Y, Song, B, Ye, J, Rao, Y and Huang, Z 2019, 'Bouchardatine suppresses rectal cancer in mice by disrupting its metabolic pathways via activating the SIRT1-PGC-1α-UCP2 axis', European Journal of Pharmacology, vol. 854, pp. 328-337.


Document type: Journal Article
Collection: Journal Articles

Title Bouchardatine suppresses rectal cancer in mice by disrupting its metabolic pathways via activating the SIRT1-PGC-1α-UCP2 axis
Author(s) Xu, Y
Song, Q
Li, C
Hu, Y
Song, B
Ye, J
Rao, Y
Huang, Z
Year 2019
Journal name European Journal of Pharmacology
Volume number 854
Start page 328
End page 337
Total pages 10
Publisher Elsevier
Abstract Cancer metabolism is an attractive target of the therapeutic strategy for cancer. The present study identified bouchardatine (Bou) as a potent suppressor of rectal cancer growth by cycle-arresting independent of apoptosis. In cultured HCT-116 rectal cancer cells, Bou increased glucose uptake/oxidation and capacity of mitochondrial oxidation. These effects were associated with an upregulation of uncoupling protein 2 (UCP2) and the activation of its upstream Sirtuin 1 (SIRT1)/(Liver kinase B1) LKB1- (Adenosine monophosphate-activated protein kinase) AMPK axis. The pivotal role of UCP2 in the cancer-suppressing effect was demonstrated by overexpressing UCP2 in HCT-116 cells with similar metabolic effects to those produced by Bou. Interestingly, Bou activated peroxisome proliferators activated receptor γ coactivator 1α (PGC-1α) and recruited it to the promoter of UCP2 in HCT-116 cells along with deacetylation (thus activation) by SIRT1. The requirement of SIRT1 for the cancer-suppressing effect through the PGC-1αUCP2 was confirmed by the reciprocal responses to Bou in HCT-116 with defected and overexpressed SIRT1. Whereas knockdown, mutation or pharmacological inhibition of SIRT1 all abolished Bou-induced deacetylation/activation of PGC-1α, the opposing effects were observed after overexpressing SIRT1. In mice, administration of Bou (50 mg/kg) also suppressed the growth of rectal cancer associated with increases the UCP2 expression and mitochondria capacity in the tumor. Collectively, our findings suggest that Bou has a therapeutic potential for the treatment of rectal cancer by disrupting the metabolic path of cancer cells via activating the PGC-1α-UCP2 axis with SIRT1 as its primary target.
Subject Metabolic Medicine
Basic Pharmacology
Chemotherapy
Keyword(s) Bouchardatine
Energy metabolism
PGC-1α
SIRT1
UCP2
DOI - identifier 10.1016/j.ejphar.2019.04.029
Copyright notice © 2019 Elsevier B.V.
ISSN 0014-2999
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