TRIM59 knockdown blocks cisplatin resistance in A549/DDP cells through regulating PTEN/AKT/HK2

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Rong He1, Hongxu Liu1

  • 1Department of Thoracic Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, PR China.

Gene
|March 14, 2020
PubMed

Insights

Tripartite motif-containing 59 (TRIM59) drives cisplatin resistance in non-small cell lung cancer (NSCLC) by increasing glycolysis. Downregulating TRIM59 restores sensitivity to cisplatin by inhibiting the PTEN/AKT/HK2 pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cisplatin is a cornerstone chemotherapy for non-small cell lung cancer (NSCLC).
  • Acquired resistance to cisplatin significantly limits its therapeutic efficacy.
  • Tripartite motif-containing 59 (TRIM59) is an oncogene implicated in chemoresistance in various cancers, including breast cancer.

Purpose of the Study:

  • To elucidate the mechanism by which TRIM59 mediates cisplatin resistance in NSCLC.
  • To investigate the role of TRIM59 in regulating glycolysis and its impact on cisplatin sensitivity.
  • To explore the potential of targeting TRIM59 as a strategy to overcome cisplatin resistance.

Main Methods:

  • Comparison of TRIM59 expression in cisplatin-sensitive (A549) and resistant (A549/DDP) NSCLC cell lines.
  • Assessment of cell apoptosis and cisplatin sensitivity following TRIM59 overexpression or knockdown.
  • Evaluation of glycolysis markers (glucose uptake, lactate production, hexokinase 2 (HK2) expression).
  • In vivo studies using a xenograft model.
  • Analysis of the PTEN/AKT/HK2 signaling pathway and TRIM59-PTEN interaction.

Main Results:

  • Cisplatin-resistant NSCLC cells (A549/DDP) exhibited significantly higher TRIM59 expression than sensitive cells (A549).
  • TRIM59 overexpression enhanced cisplatin resistance, while TRIM59 knockdown sensitized cells to cisplatin, both in vitro and in vivo.
  • TRIM59 promoted glycolysis by upregulating HK2 expression, which was reversed by TRIM59 knockdown.
  • TRIM59 knockdown led to decreased PTEN ubiquitination, suggesting its role in regulating PTEN stability and activating the AKT/HK2 pathway.
  • Both TRIM59 and HK2 were upregulated in cisplatin-resistant NSCLC tissues and positively correlated.

Conclusions:

  • TRIM59 plays a critical role in mediating cisplatin resistance in NSCLC by promoting a high glycolysis rate.
  • TRIM59 knockdown resensitizes NSCLC cells to cisplatin by inhibiting the PTEN/AKT/HK2 signaling axis.
  • Targeting TRIM59 presents a promising therapeutic strategy to overcome cisplatin resistance in NSCLC.
Keywords:
Cisplatin resistanceGlycolysisNSCLCTRIM59

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