Moselhy Jim, Suman Suman, Alghamdi Mohammed, Chandarasekharan Balaji, Das Trinath P, Houda Alatassi, Ankem Murali, Damodaran Chendil
Department of Urology, University of Louisville, KY, USA.
Department of Pathology, University of Louisville, KY, USA.
Neoplasia. 2017 Jun;19(6):451-459. doi: 10.1016/j.neo.2017.04.005. Epub 2017 May 7.
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.
我们最近证明，AKT激活在前列腺癌进展中起作用，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诱导可抑制前列腺癌进展。在此，我们研究了植物营养素睡茄内酯A（WA）对AKT驱动的前列腺癌发生的化学预防作用，该研究采用了前列腺癌的Pten条件性敲除（Pten-KO）小鼠模型。以两种不同剂量（3和5 mg/kg）进行口服WA治疗，并与赋形剂对照，持续45周。与赋形剂对照组相比，口服WA 45周可有效抑制原发性肿瘤生长。病理分析显示，接受WA治疗的小鼠器官中完全没有转移灶，而在对照肿瘤中观察到有离散的肺转移。免疫组织化学分析显示，与对照组相比，接受WA治疗的肿瘤中pAKT表达以及上皮-间质转化标志物（如β-连环蛋白和N-钙黏蛋白）下调。这一结果证实了我们先前在前列腺癌细胞培养和异种移植模型中的发现。我们的研究结果表明，每日给予一种靶向AKT激活的植物营养素，可为前列腺癌小鼠模型提供安全有效的治疗方法，且极有可能转化用于人类疾病治疗。
