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p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer

Chun-Xia Yu1,2, Zhe-Qing Peng1,2, Tao Wang1

  • 1Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China.

Acta Biochimica Et Biophysica Sinica
|December 28, 2023
PubMed

Insights

The p32/OPA1 axis drives cisplatin resistance in non-small cell lung cancer (NSCLC) by altering mitochondrial dynamics. Metformin combats this resistance by targeting p32 and OPA1, resensitizing NSCLC cells to cisplatin.

Area of Science:

  • Oncology
  • Cell Biology
  • Mitochondrial Dynamics

Background:

  • Cisplatin resistance is a significant challenge in treating non-small cell lung cancer (NSCLC).
  • Mitochondrial morphology and function are regulated by p32 and OPA1, proteins implicated in cellular processes.
  • Understanding the role of the p32/OPA1 axis in drug resistance is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC.
  • To elucidate the underlying mechanisms by which p32 and OPA1 influence mitochondrial dynamics and drug sensitivity.
  • To evaluate the potential of metformin as a therapeutic agent to overcome cisplatin resistance in NSCLC.

Main Methods:

  • Comparative analysis of p32 and OPA1 protein levels in cisplatin-sensitive and resistant NSCLC cells (A549 and A549/DDP).
  • Assessment of mitochondrial morphology (fusion/fission) and ATP generation following p32 knockdown and metformin treatment.
  • Evaluation of cell viability and apoptosis induction in response to cisplatin, metformin, and co-treatments.
  • Investigation of the effect of a p32 kinase activator (D-erythro-Sphingosine) on metformin's actions.

Main Results:

  • Elevated p32 and OPA1 levels correlate with increased mitochondrial fusion and cisplatin resistance in NSCLC cells.
  • p32 knockdown reversed these effects, promoting mitochondrial fission, reducing ATP, and enhancing cisplatin-induced apoptosis.
  • Metformin treatment downregulated p32 and OPA1, induced mitochondrial fission, decreased ATP levels, and sensitized resistant cells to cisplatin.
  • Co-administration of metformin and cisplatin significantly reduced NSCLC cell viability compared to cisplatin alone.
  • D-erythro-Sphingosine counteracted metformin's effects, highlighting the role of p32 kinase activity.

Conclusions:

  • The p32/OPA1 axis plays a critical role in acquired cisplatin resistance in NSCLC through modulation of mitochondrial dynamics.
  • Metformin resensitizes NSCLC cells to cisplatin by targeting the p32/OPA1 pathway and altering mitochondrial function.
  • Targeting p32 and mitochondrial dynamics presents a promising strategy to overcome cisplatin resistance in NSCLC treatment.
Keywords:
OPA1cisplatin resistancemetforminmitochondrial dynamicsnon-small cell lung cancerp32

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