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

Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Eiji Kashiwagi, Takashi Dejima, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Masatoshi Eto

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that protein kinase C (PKC) activation followed by Twist1 and androgen receptor (AR) induction played a critical role in castration resistance, but the precise molecular mechanism remains unknown. This study aimed to elucidate the relevant molecular mechanism, focusing on NF-κB transcription factor. We examined the activity of NF-κB after PKC inhibition, and the expression of Twist1 and AR after inhibition of NF-κB in human prostate cancer cells. We also investigated the status of PKC/NF-κB after inhibition of AR signaling in cells resistant to hormonal therapy. As a result, inhibition of PKC signaling using knockdown and smallmolecule inhibition of PKC suppressed RelA activity, while blocking NF-κB suppressed Twist1 and AR expression. Conversely, inhibition of AR signaling by androgen depletion and the novel antiandrogen enzalutamide induced PKC and RelA activation, resulting in Twist1/AR induction at the transcript level. Moreover, inhibition of NF-κB signaling prevented enzalutamide-induced Twist1 and AR induction. Finally, NF-κB was activated in both castration-resistant and enzalutamide-resistant cells. In conclusion, NF-κB signaling was responsible for Twist1 upregulation by PKC in response to AR inhibition, resulting in aberrant activation of AR. NF-κB signaling thus appears to play a critical role in promoting both castration resistance and enzalutamide resistance in PKC/Twist1 signaling in prostate cancer.

Original languageEnglish
Pages (from-to)171-180
Number of pages10
JournalEndocrine-Related Cancer
Volume24
Issue number4
DOIs
Publication statusPublished - Apr 2017

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

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