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Pregnane X receptor mediates sorafenib resistance in advanced hepatocellular carcinoma

Fan Feng1, Qiyu Jiang2, Shuang Cao3

  • 1Center for Clinical Laboratory, The 302nd Hospital of Chinese PLA, Beijing 100039, PR China; Liver Failure Treatment and Research Center, The 302nd Hospital of Chinese PLA, Beijing 100039, PR China.

Biochimica Et Biophysica Acta. General Subjects
|January 26, 2018
PubMed
Abstract

Insights

High pregnane X receptor (PXR) levels drive sorafenib resistance in liver cancer (HCC) cells. Targeting PXR offers a new therapeutic strategy to improve sorafenib treatment efficacy for HCC patients.

Area of Science:

  • Hepatocellular Carcinoma (HCC) Research
  • Drug Resistance Mechanisms
  • Molecular Oncology

Background:

  • Sorafenib is a primary treatment for advanced HCC, but its effectiveness is limited by widespread drug resistance.
  • Identifying the endogenous mechanisms of sorafenib resistance is crucial for developing better therapeutic strategies.

Purpose of the Study:

  • To investigate the role of Pregnane X receptor (PXR) in mediating sorafenib resistance in HCC.
  • To explore PXR as a potential therapeutic target for overcoming sorafenib resistance.

Main Methods:

  • Detected PXR levels using immunohistochemistry and qPCR.
  • Assessed PXR-sorafenib interaction via GST-pull down and LC-MS/MS.
  • Evaluated HCC tumor growth, metastasis, and cell survival using in vivo models, FACS, trans-well assays, and Western blot.
  • Investigated mechanisms using ChIP and luciferase reporter assays.

Main Results:

  • High PXR levels in clinical HCC specimens correlate with poor prognosis in patients treated with sorafenib.
  • Sorafenib binds to and activates PXR, leading to the development of sorafenib resistance in HCC cells.
  • PXR overexpression enhances HCC cell survival during sorafenib treatment.

Conclusions:

  • PXR plays a key role in mediating sorafenib resistance in HCC.
  • Targeting PXR presents a promising therapeutic approach to enhance HCC treatment outcomes.
Keywords:
Hepatocellular carcinomaMetabolism and clearanceMulti-drug resistancePregnane X receptorSorafenib

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