Suppression of prostate epithelial proliferation and intraprostatic progrowth signaling in transgenic mice by a new energy restriction-mimetic agent.
Suppression of prostate epithelial proliferation and intraprostatic progrowth signaling in transgenic mice by a new energy restriction-mimetic agent.
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通过新的能量限制性剂抑制前列腺上皮增殖和肉体内前体信号传导。
DOI：
10.1158/1940-6207.capr-12-0057
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Chen CS
中科院分区：
文献类型：
--
作者：
Berman-Booty LD;Chu PC;Thomas-Ahner JM;Bolon B;Wang D;Yang T;Clinton SK;Kulp SK;Chen CS
经历恶性转化的细胞通常表现出细胞代谢从氧化磷酸化向糖酵解的转变。这种糖酵解转变被称为 Warburg 效应，为通过使用饮食热量限制和能量限制模拟剂 (ERMA) 靶向糖酵解来抑制癌发生提供了机制基础。我们最近报道了一种新型 ERMA 的开发，该类 ERMA 通过抑制葡萄糖摄取，在引发饥饿相关的细胞反应和癌细胞的表观遗传变化方面表现出高效能。此类中的主要 ERMA OSU-CG5 可减少 LNCaP 前列腺癌细胞中 ATP 和 NADH 的产生。在这项研究中，我们检测了 OSU-CG5 对雄性转基因小鼠前列腺癌 (TRAMP) 小鼠癌前病变严重程度的影响。从 6 周龄到 10 周龄，每天口服 100 mg/kg OSU-CG5 导致泌尿生殖道和显微解剖的背侧、侧侧和前前列腺叶重量相对于媒介物对照出现统计学显着下降。 OSU-CG5 的抑制作用通过前列腺中 Ki67 免疫染色和增殖细胞核抗原 (PCNA) 表达的显着降低得到证明。 OSU-CG5 治疗与全身毒性证据无关。微阵列分析表明 Akt 发挥核心作用，蛋白质印迹分析显示前列腺叶中 Akt、Src、雄激素受体和胰岛素样生长因子 1 受体的磷酸化和/或表达水平降低。这些发现支持对 OSU-CG5 作为潜在化学预防剂的进一步研究。
Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent.