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Inhibition of JNK/c-Jun-ATF2 Overcomes Cisplatin Resistance in Liver Cancer through down-Regulating Galectin-1

Fan Yang1,2, Mengzhu Li1,2, Duo Xu1,2,3

  • 1Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.

International Journal of Biological Sciences
|May 22, 2023
PubMed

Insights

High c-Jun N-terminal kinase (JNK) activity drives cisplatin resistance in liver cancer by upregulating Galectin-1. Inhibiting JNK enhances DNA damage and overcomes resistance, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cisplatin (CDDP) resistance significantly limits treatment efficacy in liver cancer.
  • Understanding the molecular mechanisms of CDDP resistance is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the role of c-Jun N-terminal kinase (JNK) in mediating CDDP resistance in liver cancer.
  • To elucidate the signaling pathway involved in JNK-mediated CDDP resistance.
  • To explore JNK inhibition as a strategy to overcome CDDP resistance.

Main Methods:

  • Phosphor-kinase assays to identify activated kinases.
  • In vitro and in vivo models of CDDP-resistant liver cancer.
  • Continuous CDDP administration in vivo to simulate clinical resistance evolution.
  • In vivo bioluminescence imaging to monitor JNK activity.
  • Pharmacological and genetic inhibition of JNK.

Main Results:

  • JNK was activated in liver cancer cells upon CDDP treatment.
  • High JNK activity correlated with poor prognosis and mediated CDDP resistance.
  • JNK phosphorylated c-Jun and ATF2, upregulating Galectin-1 expression, which promotes CDDP resistance.
  • JNK activity progressively increased during simulated clinical resistance development in vivo.
  • JNK inhibition enhanced DNA damage and overcame CDDP resistance both in vitro and in vivo.

Conclusions:

  • The JNK/c-Jun-ATF2/Galectin-1 pathway is a key mediator of CDDP resistance in liver cancer.
  • Targeting JNK activity presents a promising therapeutic approach to overcome CDDP resistance.
  • The study provides a method for dynamic in vivo monitoring of molecular activity relevant to drug resistance.
Keywords:
CisplatinIn vivo bioluminescence imagingJNKLiver cancer.Resistance

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