title: Inhibition of protein kinase C/Twist1 signaling augments anticancer effects of androgen deprivation and enzalutamide in prostate cancer.
abstract: OBJECTIVE
  The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that the transcription factor Twist1, which promotes epithelial-mesenchymal transition, was involved in castration-resistant progression. Similarly, protein kinase C (PKC) has been implicated in both metastatic progression and castration resistance in prostate cancer.
  
  
  METHODS
  In this study, we aimed to elucidate the role of PKC/Twist1 signaling in castration resistance, and to apply this information to the development of a novel therapeutic concept using PKC inhibitor Ro31-8220 against prostate cancer using various prostate cancer cell lines.
  
  
  RESULTS
  Androgen deprivation and the next-generation antiandrogen enzalutamide induced PKC activation and Twist1 expression, which were reversed by the PKC inhibitor Ro31-8220. Ro31-8220 suppressed cell proliferation in androgen-dependent prostate cancer LNCaP cells, which was augmented by its combination with androgen deprivation or enzalutamide. The favorable anticancer effects of the combination of Ro31-8220 and enzalutamide were also observed in castration-resistant C4-2 and 22Rv1 cells. Furthermore, PKC phosphorylation was elevated in castration-resistant and enzalutamide-resistant cells compared with their parental cells, leading to persistent sensitivity to Ro-31-8220 in castration- and enzalutamide-resistant cells.
  
  
  CONCLUSIONS
  Taken together, these findings indicate that PKC/Twist1 signaling contributes to castration resistance as well as enzalutamide resistance in prostate cancer, and suggest that therapeutics targeting PKC/Twist1 signaling, such as PKC inhibitors, represent a promising novel therapeutic strategy for prostate cancer, especially castration-resistant prostate cancer, when combined with enzalutamide.
authors.affiliation: Authors' Affiliations: Departments of Urology and Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Imada
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.forename: YooHyun
authors.initials: Y
authors.lastname: Song
authors.forename: Junichi
authors.initials: J
authors.lastname: Inokuchi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009570:Nitriles; D009687:Nuclear Proteins / Q000378:metabolism*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D009570:Nitriles; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011944:Receptors, Androgen; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D010669:Phenylthiohydantoin; C540278:enzalutamide; D011493:Protein Kinase C; C064758:Ro 31-8220