Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism.
Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism.
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Kavalactone Kawain 通过抑制 mTOR 信号传导和改变癌症代谢来阻止 UPII 突变 Ha-Ras 小鼠的尿路上皮肿瘤发生。
DOI：
10.3390/molecules28041666
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发表时间：
2023-02-09
期刊：
影响因子：
4.6
通讯作者：
Zi, Xiaolin
中科院分区：
文献类型：
--
作者：
Liu, Zhongbo;Song, Liankun;Xie, Jun;Wu, Xue-Ru;Gin, Greg E.;Wang, Beverly;Uchio, Edward;Zi, Xiaolin
UPII突变型Ha-ras转基因小鼠发生尿路上皮增生和低度乳头状癌，其模拟人类非肌肉浸润性膀胱癌（NMIBC）。我们调查的影响和机制的卡瓦，卡瓦植物中的主要卡瓦内酯，对致癌Ha-ras驱动的尿路上皮癌在这些小鼠。在6周龄时用载体对照或kawain（6 g/kg）配制的食物喂养小鼠约5个月。78%或更多的喂食卡瓦因食物的小鼠存活超过6个月，而只有32%的喂食对照食物的雄性小鼠存活，（p = 0.0082）。与喂食对照饮食的小鼠相比，喂食卡瓦酒饮食的UPII突变Ha-ras转基因小鼠的平均湿膀胱重量（肿瘤负荷的替代物）降低了约56%（p = 0.035）。卡汶饮食也显着降低了UPII突变Ha-ras转基因小鼠肾积水和血尿的发生。组织学检查和免疫组织化学分析显示，与卡瓦因处理的小鼠相比，载体对照处理的小鼠在膀胱中显示出更多的尿路上皮癌和Ki 67阳性细胞。与喂食对照饮食的小鼠相比，喂食卡瓦因食物的小鼠的膀胱肿瘤样品的总体代谢谱显示出显着更多的5-羟色胺富集和木酮糖，前列腺素A2，D2和E2的丰度较低，表明葡萄糖向磷酸戊糖途径（PPP）的分流减少并减少炎症。此外，卡瓦因选择性地抑制人膀胱癌细胞系的生长，显著抑制4 E-BP 1表达和rpS 6磷酸化。这些观察结果表明，通过重新连接肿瘤细胞的代谢程序，卡瓦因消费对膀胱癌预防的潜在影响。
UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months. Seventy-eight percent of the mice or more fed with kawain food survived more than six months of age, whereas only 32% control food-fed male mice survived, (p = 0.0082). The mean wet bladder weights (a surrogate for tumor burden) of UPII-mutant Ha-ras transgenic mice with kawain diet was decreased by approximately 56% compared to those fed with the control diet (p = 0.035). The kawain diet also significantly reduced the occurrence of hydronephrosis and hematuria in UPII-mutant Ha-ras transgenic mice. Histological examination and immunohistochemistry analysis revealed that vehicle control-treated mice displayed more urothelial carcinoma and Ki67-positive cells in the bladder compared to kawain treated mice. Global metabolic profiling of bladder tumor samples from mice fed with kawain food showed significantly more enrichment of serotonin and less abundance of xylulose, prostaglandin A2, D2 and E2 compared to those from control diet-fed mice, suggesting decreased shunting of glucose to the pentose phosphate pathway (PPP) and reduced inflammation. In addition, kawain selectively inhibited the growth of human bladder cancer cell lines with a significant suppression of 4E-BP1 expression and rpS6 phosphorylation. These observations indicate a potential impact of kawain consumption on bladder cancer prevention by rewiring the metabolic programs of the tumor cells.
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影响因子：
11.2
作者：
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影响因子：
5.2
作者：
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作者：
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作者：
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DOI：
10.3390/molecules22030462
发表时间：
2017-03-14
期刊：
Molecules (Basel, Switzerland)
影响因子：
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通讯作者：
Zi X