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p53 Affects PGC1α Stability Through AKT/GSK-3β to Enhance Cisplatin Sensitivity in Non-Small Cell Lung Cancer

Xinyue Deng1, Yang Li1, Shuang Gu2

  • 1Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.

Frontiers in Oncology
|September 25, 2020
PubMed

Insights

Tumor suppressor p53 dysfunction in non-small cell lung cancer (NSCLC) leads to drug resistance. This study reveals p53 regulates peroxisome proliferator-activated receptor coactivator (PGC1α) stability, impacting NSCLC chemosensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Drug resistance in non-small cell lung cancer (NSCLC) is a major clinical challenge.
  • Tumor suppressor p53 dysfunction and its role in regulating mitochondrial proteins like PGC1α are implicated in NSCLC.
  • The precise interaction mechanism between p53 and PGC1α in NSCLC remains unclear.

Purpose of the Study:

  • To investigate the signaling pathway between p53 and PGC1α in NSCLC.
  • To elucidate the role of p53-PGC1α interaction in regulating anti-tumor drug efficacy.
  • To explore potential therapeutic strategies targeting this pathway for improved NSCLC treatment.

Main Methods:

  • Analysis of p53 and PGC1α expression in NSCLC patient survival data.
  • In vitro experiments using NSCLC cell lines (NCI-H1299) with varying p53 and PGC1α levels.
  • Investigation of PGC1α stability regulation via the ubiquitin proteasome pathway, including AKT and GSK-3β signaling.

Main Results:

  • Low p53 and high PGC1α expression correlated with reduced survival in NSCLC patients.
  • p53-null NSCLC cells exhibited high PGC1α levels and cisplatin (CDDP) resistance, which was reversed by PGC1α knockdown.
  • p53 was found to decrease PGC1α stability through the AKT/GSK-3β pathway.

Conclusions:

  • p53 regulates PGC1α stability via the AKT/GSK-3β signaling pathway.
  • Modulating p53-PGC1α interaction may enhance NSCLC chemosensitivity to drugs like cisplatin.
  • Targeting the p53-PGC1α axis presents a potential therapeutic avenue for overcoming drug resistance in NSCLC.
Keywords:
AKTCDDPGSK-3βPGC1αmitochondrial functionnon-small cell lung cancerp53

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