Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms.
Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms.
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DOI：
10.2337/db14-1132
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发表时间：
2015-05
期刊：
影响因子：
7.7
通讯作者：
Hursting SD
中科院分区：
文献类型：
--
作者：
Cifarelli V;Lashinger LM;Devlin KL;Dunlap SM;Huang J;Kaaks R;Pollak MN;Hursting SD
二甲双胍治疗与2型糖尿病患者胰腺癌（PC）风险降低和预后改善相关，但二甲双胍在糖尿病前期状态下抑制PC生长的机制尚不清楚。我们在饮食诱导的肥胖（DIO）C57 BL/6小鼠中使用Panc 02胰腺肿瘤细胞移植模型，比较二甲双胍和雷帕霉素（mTOR）直接哺乳动物靶点抑制剂雷帕霉素对PC生长、葡萄糖调节、mTOR通路信号传导和候选microRNA（miR）表达的影响。在DIO/前驱糖尿病小鼠中，二甲双胍和雷帕霉素显著降低胰腺肿瘤生长和mTOR相关信号传导。雷帕霉素的作用集中在降低mTOR调节的生长和存活信号，包括增加let-7 b和细胞周期调节miR的表达。二甲双胍（但不是雷帕霉素）降低了葡萄糖和胰岛素水平以及miR-34 a及其直接靶点Notch、Slug和Snail的表达。二甲双胍还减少了体外Panc 02肿瘤球的数量和大小，并抑制了球体中Notch的表达。我们的研究结果表明，二甲双胍和雷帕霉素都可以通过共同和不同的机制抑制肥胖，糖尿病前期小鼠胰腺肿瘤的生长。Metabolic和直接mTOR抑制剂，单独或可能组合，代表了打破糖尿病-PC联系的有希望的干预策略。
Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin’s PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling. The rapamycin effects centered on decreased mTOR-regulated growth and survival signaling, including increased expression of let-7b and cell cycle–regulating miRs. Metformin (but not rapamycin) reduced glucose and insulin levels and expression of miR-34a and its direct targets Notch, Slug, and Snail. Metformin also reduced the number and size of Panc02 tumor spheres in vitro and inhibited the expression of Notch in spheroids. Our results suggest that metformin and rapamycin can both inhibit pancreatic tumor growth in obese, prediabetic mice through shared and distinct mechanisms. Metformin and direct mTOR inhibitors, alone or possibly in combination, represent promising intervention strategies for breaking the diabetes-PC link.
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DOI：
10.1158/1940-6207.capr-12-0034
发表时间：
2012-07
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Dunlap SM;Chiao LJ;Nogueira L;Usary J;Perou CM;Varticovski L;Hursting SD
通讯作者：
Hursting SD
影响因子：
29.4
作者：
Li, Lei;Li, Zhaoshen;Xie, Keping
通讯作者：
Xie, Keping
影响因子：
20.3
作者：
Decker, T;Hipp, S;Peschel, C
通讯作者：
Peschel, C
影响因子：
11.2
作者：
Bao, Bin;Wang, Zhiwei;Li, Yiwei;Kong, Dejuan;Ali, Shadan;Banerjee, Sanjeev;Ahmad, Aamir;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.
DOI：
10.1158/1940-6207.capr-11-0299
发表时间：
2012-03
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Bao B;Wang Z;Ali S;Ahmad A;Azmi AS;Sarkar SH;Banerjee S;Kong D;Li Y;Thakur S;Sarkar FH
通讯作者：
Sarkar FH