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Protein kinase C regulates Twist1 expression via NF-κB in prostate cancer.
- Source :
-
Endocrine-related cancer [Endocr Relat Cancer] 2017 Apr; Vol. 24 (4), pp. 171-180. Date of Electronic Publication: 2017 Feb 21. - Publication Year :
- 2017
-
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 small-molecule 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.<br /> (© 2017 Society for Endocrinology.)
- Subjects :
- Androgen Antagonists pharmacology
Benzamides
Cell Line, Tumor
Humans
Male
NF-kappa B genetics
Nitriles
Nuclear Proteins genetics
Phenylthiohydantoin analogs & derivatives
Phenylthiohydantoin pharmacology
Prostatic Neoplasms, Castration-Resistant genetics
Protein Kinase C-epsilon genetics
Receptors, Androgen genetics
Transcription Factor RelA genetics
Transcription Factor RelA metabolism
Twist-Related Protein 1 genetics
NF-kappa B metabolism
Nuclear Proteins metabolism
Prostatic Neoplasms, Castration-Resistant metabolism
Protein Kinase C-epsilon metabolism
Twist-Related Protein 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1479-6821
- Volume :
- 24
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Endocrine-related cancer
- Publication Type :
- Academic Journal
- Accession number :
- 28223364
- Full Text :
- https://doi.org/10.1530/ERC-16-0384