Endocrine Related Cancer, 2012, 19(6):759-777.

Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization

Benjamin A. Mooso, Ruth L. Vinall, Clifford G. Tepper, et al

VA Northern California Health Care System, Mather, California, USA; et al

As prostate cancer (CaP) is regulated by androgen receptor (AR) activity, metastatic CaP is treated with androgen deprivation therapy (ADT). Despite initial response, patients on ADT eventually progress to castration-resistant CaP (CRPC), which is currently incurable. We previously showed that cleavage of the 280 kDa structural protein Filamin A (FlnA) to a 90 kDa fragment, and nuclear localization of the cleaved product, sensitized CRPC cells to ADT. Hence, treatment promoting FlnA nuclear localization would enhance androgen responsiveness. Here, we show that FlnA nuclear localization induced apoptosis in CRPC cells during ADT, identifying it as a treatment tool in advanced CaP. Significantly, the natural product genistein combined polysaccharide (GCP) had a similar effect. Investigation of the mechanism of GCP-induced apoptosis showed that GCP induced FlnA cleavage and nuclear localization and that apoptosis resulting from GCP treatment was mediated by FlnA nuclear localization. Two main components of GCP are genistein and daidzein: the ability of GCP to induce G2 arrest was due to genistein whereas sensitivity to ADT stemmed from daidzein; hence, both were needed to mediate GCP's effects. FlnA cleavage is regulated by its phosphorylation; we show that ADT enhanced FlnA phosphorylation, which prevented its cleavage, whereas GCP inhibited FlnA phosphorylation, thereby sensitizing CaP cells to ADT. In a mouse model of CaP recurrence, GCP, but not vehicle, impeded relapse following castration, indicating that GCP, when administered with ADT, interrupted the development of CRPC. These results demonstrate the efficacy of GCP in promoting FlnA nuclear localization and enhancing androgen responsiveness in CaP.

英国《内分泌相关癌症》，2012年11月

通过诱导细丝蛋白 A细胞核定位提高前列腺癌中雄激素缺乏的效果

班杰明 A 穆森，露丝 L 维纳尔，克利福德 G 泰伯等

美国弗吉尼亚州北加州卫生保健系统等

因为前列腺癌 (CaP) 受雄激素受体 (AR) 活性调节，所以用雄激素剥夺疗法 (ADT) 治疗转移性CaP。不管最初响应是什么，患者对ADT 的响应最终会发展成去势难治性(CRPC) ，目前不可治愈。我们以前研究280 kDa 结构蛋白细丝蛋白 A (FlnA)的解离为 90 kDa 的片段，并且解离产物进行核定位， 使CRPC 细胞对ADT敏感。因此，提高 FlnA 核定位的疗法将增强雄激素的响应能力。在这里，我们表明，在 ADT过程中FlnA 核定位诱导CRPC 细胞凋亡，确认其可以作为一种治疗晚期CaP的工具。重要的是，天然产物金雀异黄素联合多糖 (GCP) 具有相似的效果。对GCP 诱导细胞凋亡机理的研究表明，GCP 诱导 FlnA 解离和核定位并且 GCP 治疗引起的细胞凋亡由 FlnA 核定位调节。GCP 的两个主要成分是金雀异黄素和大豆黄酮︰ GCP 能够诱导 G2期阻滞的能力是由于金雀异黄素而 ADT 的敏感性则源于大豆黄酮；因此，两者都需要调节 GCP 的作用。FlnA 解离受其磷酸化调节；我们表明，ADT 提高 FlnA 磷酸化，阻止其裂解，而 GCP 抑制 FlnA 磷酸化，从而使CaP细胞对 ADT敏感。在CaP再复发的小鼠模型中，GCP，但不是空白样，在去势以后阻碍了复发，说明 GCP，当给药ADT时，中断CRPC的发展。这些结果证明GCP在促进 FlnA 核定位和增强雄激素反应性方面的疗效。