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FXYD5 promotes sorafenib resistance through the Akt/mTOR signaling pathway in hepatocellular carcinoma

Xiang-Peng Tan1, Ben-Han Xiong2, Yuan-Xu Zhang2

  • 1The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China.

European Journal of Pharmacology
|August 17, 2022
PubMed

Insights

FXYD5 protein promotes hepatocellular carcinoma (HCC) chemoresistance by activating the Akt/mTOR pathway, suggesting FXYD5 as a potential therapeutic target for overcoming sorafenib resistance in HCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor chemoresistance is a significant obstacle in cancer therapy, particularly in hepatocellular carcinoma (HCC).
  • Sorafenib resistance in HCC limits treatment efficacy, necessitating identification of resistance mechanisms.
  • FXYD5 (FXYD domain-containing ion transport regulator 5) has not been previously linked to sorafenib resistance in HCC.

Purpose of the Study:

  • To investigate the role of FXYD5 in sorafenib resistance in hepatocellular carcinoma (HCC).
  • To elucidate the underlying molecular mechanism by which FXYD5 influences HCC chemoresistance.
  • To evaluate FXYD5 as a potential therapeutic target for overcoming sorafenib resistance in HCC.

Main Methods:

  • Comparative analysis of FXYD5 expression in sorafenib-resistant HCC cells versus sensitive cells and HCC tissues versus adjacent tissues.
  • Manipulation of FXYD5 expression (overexpression and downregulation) in HCC cell lines to assess its impact on sorafenib sensitivity.
  • Investigation of the Akt/mTOR signaling pathway activation in relation to FXYD5 expression.
  • Correlation analysis between p-Akt and FXYD5 expression levels in HCC tissues.
  • Assessment of Akt inhibitor (MK2206) efficacy in combination with sorafenib.

Main Results:

  • FXYD5 is significantly upregulated in sorafenib-resistant HCC cells and in HCC tissues compared to normal tissues.
  • Downregulation of FXYD5 restores sorafenib sensitivity in resistant HCC cells, while its overexpression reduces sensitivity.
  • The Akt/mTOR signaling pathway is aberrantly activated in sorafenib-resistant HCC cells, and this activation is linked to FXYD5 expression.
  • p-Akt expression is positively correlated with FXYD5 expression in HCC tissues.
  • Inhibition of Akt signaling enhances sorafenib sensitivity in HCC cells.

Conclusions:

  • FXYD5 promotes sorafenib resistance in HCC by activating the Akt/mTOR signaling pathway.
  • The FXYD5/Akt/mTOR signaling axis is crucial in mediating HCC chemoresistance.
  • FXYD5 represents a promising novel therapeutic target for enhancing sorafenib efficacy in HCC treatment.
Keywords:
Akt/mTOR signaling pathwayFXYD5HCCSorafenib resistance

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