Rhamnetin decelerates the elimination and enhances the antitumor effect of the molecular-targeting agent sorafenib in hepatocellular carcinoma cells via the miR-148a/PXR axis

The pregnane X receptor (PXR) mediates the resistance of sorafenib in hepatocellular carcinoma (HCC) by promoting the clearance or elimination of sorafenib via the drug resistance-related downstream genes of the PXR. Previously, we revealed that rhamnetin (a flavonoid functioning as an inhibitor of...

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Bibliographic Details
Published in:Food & function 2021-03, Vol.12 (6), p.2404-2417
Main Authors: Li, Boan, Feng, Fan, Jia, Hui, Jiang, Qiyu, Cao, Shuang, Wei, Ling, Zhang, Yingshi, Lu, Jincai
Format: Article
Language:English
Subjects:
Acetylation
Anticancer properties
Antitumor activity
Cytochrome
Cytochromes
Deceleration
Drug resistance
Flavonoids
Gene expression
Genes
Hepatocellular carcinoma
Liver cancer
MDR1 protein
Metabolism
MicroRNAs
miRNA
Multidrug resistance
P-Glycoprotein
p53 Protein
Ribonucleic acid
RNA
Sensitivity enhancement
SIRT1 protein
Transcription activation
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Summary:The pregnane X receptor (PXR) mediates the resistance of sorafenib in hepatocellular carcinoma (HCC) by promoting the clearance or elimination of sorafenib via the drug resistance-related downstream genes of the PXR. Previously, we revealed that rhamnetin (a flavonoid functioning as an inhibitor of sirtuin (Sirt)1) could inhibit expression of the downstream gene of the PXR: multidrug resistance 1 (mdr-1). However, how rhamnetin regulates the PXR pathway in HCC cells is not known. Here, we demonstrated that rhamnetin decelerated elimination of the molecular-targeting agent sorafenib in HCC cells via the microRNA (miR)-148a/PXR axis. Rhamnetin treatment decreased expression of the drug resistance-related downstream genes of PXR (cyp3a4 [cytochrome P-450] or mdr-1 [multi-drug resistance 1]), which mediate the metabolism or elimination of sorafenib in HCC cells. Mechanistically, rhamnetin increased expression of miR-148a (which is tumor-suppressive) in a P53-dependent manner, leading to inhibition of PXR expression and decrease in expression of its downstream genes. Rhamnetin enhanced miRNA-148a transcription by repressing Sirt1 activation to enhance acetylation at residue-373 of P53. Rhamnetin treatment decelerated the metabolic clearance of sorafenib in HCC cells and enhanced the sensitivity of HCC cells to sorafenib. Our results suggest that rhamnetin could be a potential agent for overcoming sorafenib resistance in HCC treatment.
ISSN:2042-6496
2042-650X
DOI:10.1039/d0fo02270e