We recently demonstrated that AKT activation plays a role in prostate cancer progression and inhibits the pro-apoptotic function of FOXO3a and Par-4. AKT inhibition and Par-4 induction suppressed prostate cancer progression in preclinical models. Here, we investigate the chemopreventive effect of the phytonutrient Withaferin A (WA) on AKT-driven prostate tumorigenesis in a Pten conditional knockout (Pten-KO) mouse model of prostate cancer. Oral WA treatment was carried out at two different doses (3 and 5 mg/kg) and compared to vehicle over 45 weeks. Oral administration of WA for 45 weeks effectively inhibited primary tumor growth in comparison to vehicle controls. Pathological analysis showed the complete absence of metastatic lesions in organs from WA-treated mice, whereas discrete metastasis to the lungs was observed in control tumors. Immunohistochemical analysis revealed the down-regulation of pAKT expression and epithelial-to-mesenchymal transition markers, such as β-catenin and N-cadherin, in WA-treated tumors in comparison to controls. This result corroborates our previous findings from both cell culture and xenograft models of prostate cancer. Our findings demonstrate that the daily administration of a phytonutrient that targets AKT activation provides a safe and effective treatment for prostate cancer in a mouse model with strong potential for translation to human disease.

中文翻译：

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Withaferin A抑制PTEN缺陷型前列腺癌小鼠模型中的前列腺癌发生。

我们最近证明，AKT激活在前列腺癌的进展中起作用，并抑制FOXO3a和Par-4的促凋亡功能。在临床前模型中，AKT抑制和Par-4诱导抑制了前列腺癌的进展。在这里，我们调查在Pten条件性基因敲除（Pten-KO）小鼠前列腺癌模型中，植物营养素Withaferin A（WA）对AKT驱动的前列腺肿瘤发生的化学预防作用。口服WA治疗以两种不同的剂量（3和5 mg / kg）进行，并与赋形剂进行了45周比较。与赋形剂对照相比，口服WA 45周可有效抑制原发性肿瘤的生长。病理分析表明，在接受WA治疗的小鼠的器官中完全没有转移灶，而在对照肿瘤中则观察到了向肺的离散转移。免疫组织化学分析显示，与对照组相比，在WA治疗的肿瘤中pAKT表达和上皮-间质转化标记物（例如β-catenin和N-cadherin）下调。该结果证实了我们先前从细胞培养和前列腺癌异种移植模型中得到的发现。我们的发现表明，每天施用靶向AKT激活的植物营养素可为小鼠模型中的前列腺癌提供安全有效的治疗方法，并具有转化为人类疾病的巨大潜力。该结果证实了我们先前从细胞培养和前列腺癌异种移植模型中得到的发现。我们的发现表明，每天施用靶向AKT激活的植物营养素可为小鼠模型中的前列腺癌提供安全有效的治疗方法，并具有转化为人类疾病的巨大潜力。该结果证实了我们先前从细胞培养和前列腺癌异种移植模型中得到的发现。我们的发现表明，每天施用靶向AKT激活的植物营养素可为小鼠模型中的前列腺癌提供安全有效的治疗方法，并具有转化为人类疾病的巨大潜力。