Inhibition of XPR1-dependent phosphate efflux induces mitochondrial dysfunction: A potential molecular target therapy for hepatocellular carcinoma?

Mol Carcinog. 2024 Dec;63(12):2332-2345. doi: 10.1002/mc.23812. Epub 2024 Aug 13.

Abstract

Xenotropic and polytropic retrovirus receptor 1 (XPR1) is the only known transporter associated with Pi efflux in mammals, and its impact on tumor progression is gradually being revealed. However, the role of XPR1 in hepatocellular carcinoma (HCC) is unknown. A bioinformatics screen for the phosphate exporter XPR1 was performed in HCC patients. The expression of XPR1 in clinical specimens was analyzed using quantitative real-time PCR, Western blot analysis, and immunohistochemical assays. Knockdown of the phosphate exporter XPR1 was performed by shRNA transfection to investigate the cellular phenotype and phosphate-related cytotoxicity of the Huh7 and HLF cell lines. In vivo tests were conducted to investigate the tumorigenicity of HCC cells xenografted into immunocompromised mice after silencing XPR1. Compared with that in paracancerous tissue, XPR1 expression in HCC tissues was markedly upregulated. High XPR1 expression significantly correlated with poor patient survival. Silencing of XPR1 leads to decreased proliferation, migration, invasion, and colony formation in HCC cells. Mechanistically, knockdown of XPR1 causes an increase in intracellular phosphate levels; mitochondrial dysfunction characterized by reduced mitochondrial membrane potential and adenosine triphosphate levels; increased reactive oxygen species levels; abnormal mitochondrial morphology; and downregulation of key mitochondrial fusion, fission, and inner membrane genes. This ultimately results in mitochondria-dependent apoptosis. These findings reveal the prognostic value of XPR1 in HCC progression and, more importantly, suggest that XPR1 might be a potential therapeutic target.

Keywords: XPR1; hepatocellular carcinoma; mitochondrion dysfunction; phosphate transporter; prognostic marker; therapeutic target.

MeSH terms

  • Animals
  • Apoptosis
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Male
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Nude
  • Middle Aged
  • Mitochondria / metabolism
  • Molecular Targeted Therapy
  • Phosphates* / metabolism
  • Prognosis
  • Reactive Oxygen Species / metabolism
  • Xenograft Model Antitumor Assays
  • Xenotropic and Polytropic Retrovirus Receptor*

Substances

  • Xenotropic and Polytropic Retrovirus Receptor
  • XPR1 protein, human
  • Phosphates
  • Reactive Oxygen Species