CDK12 Inactivation Attenuates Prostate Cancer Progression by Inhibiting BNIP3-Mediated Mitophagy

Area of Science:

• Cellular Biology
• Molecular Oncology
• Mitochondrial Dynamics

Background:

• Mitophagy is crucial for cellular homeostasis but can promote drug resistance in cancer.
• CDK12 is a known regulator of prostate cancer (PCa) cell survival during enzalutamide treatment.
• The precise mechanism by which CDK12 influences enzalutamide resistance is not fully understood.

Purpose of the Study:

• To investigate the role of CDK12 in regulating mitophagy under mitochondrial stress in PCa.
• To determine if CDK12 modulates PCa cell resistance to enzalutamide.
• To elucidate the molecular pathway linking CDK12, mitophagy, and enzalutamide response.

Main Methods:

• Utilized in vitro PCa cell models.
• Assessed mitophagy impairment via CDK12 knockdown and pharmacological inhibition (THZ531) after enzalutamide and CCCP treatment.
• Investigated the transcriptional regulation of BNIP3 by FOXO3 in response to CDK12 inhibition.

Main Results:

• CDK12 inhibition (knockdown or THZ531) significantly impaired mitophagy induced by enzalutamide and CCCP.
• CDK12 inhibition disrupted FOXO3-induced BNIP3 transcription.
• This disruption prevented receptor-mediated mitophagy, sensitizing PCa cells to enzalutamide.

Conclusions:

• Identified the CDK12-FOXO3-BNIP3 pathway as a novel regulator of mitophagy under mitochondrial stress.
• Demonstrated CDK12's role in maintaining mitochondrial function and promoting PCa cell survival during enzalutamide treatment.
• Highlighted the therapeutic potential of targeting the CDK12-BNIP3-mitophagy axis with antiandrogen therapies to overcome PCa drug resistance.