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Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy

Yang Meng1, Lei Qiu1, Xinyi Zeng1,2

  • 1Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

Signal Transduction and Targeted Therapy
|December 8, 2022
PubMed

Insights

This study reveals how CRL4CUL4A/DDB1 impacts ovarian cancer chemoresistance by controlling mitochondrial dynamics and mitophagy. Disrupting this complex may offer a new therapeutic strategy for ovarian cancer.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Chemoresistance remains a major challenge in ovarian cancer (OC) treatment.
  • Mitochondria play a key role in chemotherapy response, with dysregulated mitochondrial dynamics linked to OC.
  • The precise mechanisms linking mitochondrial dynamics to OC chemoresistance are not fully understood.

Purpose of the Study:

  • To elucidate the role of the CRL4CUL4A/DDB1 E3 ubiquitin ligase complex in regulating mitochondrial dynamics and mitophagy in ovarian cancer.
  • To investigate how CRL4CUL4A/DDB1 influences chemoresistance in OC cells.
  • To explore potential therapeutic strategies targeting CRL4CUL4A/DDB1 and mitophagy for OC treatment.

Main Methods:

  • CRISPR-Cas9 mediated depletion of CRL4CUL4A/DDB1 in OC cells.
  • Analysis of mitochondrial fission and fusion proteins.
  • Assessment of mitophagy using the Parkin-PINK1 pathway.
  • Cell proliferation assays and autophagy inhibition experiments.

Main Results:

  • CRL4CUL4A/DDB1 depletion enhanced mitochondrial fission via AMPKα and MFF phosphorylation, promoting DRP1 recruitment to mitochondria.
  • Loss of CRL4CUL4A/DDB1 stimulated mitophagy through the Parkin-PINK1 pathway, leading to the degradation of fragmented mitochondria.
  • Inhibition of OC cell proliferation was observed upon CRL4CUL4A/DDB1 loss, with partial reversal by autophagy inhibition.

Conclusions:

  • CRL4CUL4A/DDB1 plays a critical role in regulating mitochondrial dynamics and mitophagy, thereby influencing ovarian cancer chemoresistance.
  • Targeting CRL4CUL4A/DDB1 and mitophagy presents a potential therapeutic avenue to overcome chemoresistance in ovarian cancer.

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