Authors' Affiliations: Departments of Urology and Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Clin Cancer Res. 2014 Feb 15;20(4):951-61. doi: 10.1158/1078-0432.CCR-13-1809. Epub 2013 Dec 18.
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.
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.
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.
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.
前列腺癌向转移性和去势抵抗性疾病的进展代表了一个关键步骤。我们之前表明，转录因子 Twist1 促进上皮-间质转化，参与了去势抵抗性进展。同样，蛋白激酶 C（PKC）已被牵涉到前列腺癌的转移进展和去势抵抗。
在这项研究中，我们旨在阐明 PKC/Twist1 信号在去势抵抗中的作用，并将这一信息应用于开发一种新的治疗概念，使用 PKC 抑制剂 Ro31-8220 针对各种前列腺癌细胞系的前列腺癌。
雄激素剥夺和下一代抗雄激素恩杂鲁胺诱导了 PKC 的激活和 Twist1 的表达，这被 PKC 抑制剂 Ro31-8220 逆转。Ro31-8220 抑制了雄激素依赖性前列腺癌细胞系 LNCaP 的细胞增殖，其与雄激素剥夺或恩杂鲁胺联合使用时增强了这种抑制作用。Ro31-8220 与恩杂鲁胺联合使用在去势抵抗性 C4-2 和 22Rv1 细胞中也观察到了有利的抗癌作用。此外，与亲本细胞相比，去势抵抗性和恩杂鲁胺耐药性细胞中的 PKC 磷酸化水平升高，导致去势和恩杂鲁胺耐药性细胞对 Ro-31-8220 持续敏感。
综上所述，这些发现表明 PKC/Twist1 信号通路参与了前列腺癌的去势抵抗和恩杂鲁胺耐药，表明针对 PKC/Twist1 信号通路的治疗，如 PKC 抑制剂，当与恩杂鲁胺联合使用时，代表了一种有前途的治疗前列腺癌的新策略，特别是去势抵抗性前列腺癌。
