Protein kinase C regulates Twist1 expression via NF-κB in prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling Pathways

Background:

• Prostate cancer progression to metastatic and castration-resistant disease is a critical clinical challenge.
• Protein kinase C (PKC) activation, followed by Twist1 and androgen receptor (AR) induction, is implicated in castration resistance, but the mechanism is unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which PKC activation leads to castration resistance, focusing on the role of nuclear factor-kappa B (NF-κB) transcription factor.
• To investigate the interplay between PKC, NF-κB, Twist1, and AR signaling in prostate cancer cells, particularly in response to androgen receptor signaling inhibition.

Main Methods:

• Examined NF-κB activity following PKC inhibition and Twist1/AR expression after NF-κB inhibition in prostate cancer cells.
• Investigated PKC/NF-κB status after inhibiting AR signaling in hormone-therapy-resistant cells.
• Utilized knockdown strategies and small-molecule inhibitors for PKC and NF-κB, alongside androgen depletion and enzalutamide treatment.

Main Results:

• PKC inhibition suppressed NF-κB (RelA) activity, and NF-κB inhibition blocked Twist1 and AR expression.
• Inhibition of AR signaling (androgen depletion, enzalutamide) induced PKC and NF-κB (RelA) activation, leading to increased Twist1/AR transcript levels.
• NF-κB inhibition prevented enzalutamide-induced Twist1 and AR upregulation; NF-κB was activated in castration-resistant and enzalutamide-resistant cells.

Conclusions:

• NF-κB signaling mediates Twist1 upregulation by PKC in response to AR inhibition, causing aberrant AR activation.
• NF-κB signaling plays a critical role in promoting both castration resistance and enzalutamide resistance within the PKC/Twist1 signaling axis in prostate cancer.