Inhibition of protein kinase C/Twist1 signaling augments anticancer effects of androgen deprivation and enzalutamide in prostate cancer

Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Kenjiro Imada, Eiji Kashiwagi, YooHyun Song, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito
Clinical Cancer Research 2014 February 15, 20 (4): 951-61

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.

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