title: Protein kinase C regulates Twist1 expression via NF-κB in prostate cancer.
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.
authors.affiliation: Department of UrologyGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan shiota@uro.med.kyushu-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.affiliation: Department of UrologyGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.affiliation: Department of UrologyGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Department of UrologyGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.affiliation: Department of UrologyGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Dejima
authors.affiliation: Department of UrologyGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Inokuchi
authors.affiliation: Department of UrologyGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.affiliation: Department of Clinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.affiliation: Department of UrologyGraduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Eto
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D001549:Benzamides; D016328:NF-kappa B; D009570:Nitriles; D009687:Nuclear Proteins; C498143:RELA protein, human; D011944:Receptors, Androgen; C103173:TWIST1 protein, human; D051996:Transcription Factor RelA; D051879:Twist-Related Protein 1; D010669:Phenylthiohydantoin; C540278:enzalutamide; D051744:Protein Kinase C-epsilon
keywords: NF-κB; Twist1; androgen receptor; prostate cancer; protein kinase C