Effect of p53 on pancreatic cancer-glucose tolerance abnormalities by regulating transglutaminase 2 in resistance to glucose metabolic stress.
Effect of p53 on pancreatic cancer-glucose tolerance abnormalities by regulating transglutaminase 2 in resistance to glucose metabolic stress.
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p53通过调节转谷氨酰胺酶2抵抗葡萄糖代谢应激对胰腺癌糖耐量异常的影响
DOI：
10.18632/oncotarget.19402
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发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
Yuan Y
中科院分区：
文献类型：
--
作者：
Su X;He X;Ben Q;Wang W;Song H;Ye Q;Zang Y;Li W;Chen P;Yao W;Yuan Y
胰腺导管腺癌（PanCa）是一种极其致命的疾病，其特征在于高达70%的病例中存在p53突变。我们以往的研究证实，高血糖可能是PanCa早期诊断的第一个临床表现。在这篇文章中，我们发现，在肿瘤细胞中靶向敲除TG 2或p53导致细胞存活率下降，而这种现象被取消了TG 2和p53的联合抑制。我们观察到TG 2或p53的抑制通过细胞内活性氧（ROS）通路和Bcl-2的诱导敏化葡萄糖剥夺抵抗。此外，为了了解TG 2和p53联合干扰的胰腺癌细胞是否对胰腺β细胞具有可能的影响，我们进行了比较TG 2和p53联合干扰的胰腺癌细胞和胰腺β细胞的研究。我们发现TG 2和p53联合干扰的胰腺癌细胞上清液降低了胰腺β细胞的细胞存活率。在建立原位胰腺癌小鼠模型后，我们发现TG 2和p53联合干扰的胰腺癌小鼠模型中存在葡萄糖耐量异常，表明胰腺癌中β细胞损伤的可能机制。综上所述，我们的研究结果确立了TG 2和p53在胰腺癌细胞葡萄糖剥夺反应中的作用。TG 2和p53之间的关系提示了葡萄糖耐量异常相关胰腺癌的可能机制，并可能具有癌症治疗和诊断的治疗潜力。
Pancreatic ductal adenocarcinoma (PanCa) is an extremely lethal disease characterized by mutations of p53 in up to 70% of cases. Our previous studies have confirmed that hyperglycemia may be the first clinical manifestation for the early diagnosis of PanCa. In this article, we showed that targeted knockdown of TG2 or p53 in tumor cells led to decreased cell survival in response to glucose deprivation, while this phenomenon was abolished by combined inhibition of TG2 and p53. We observed that inhibition of TG2 or p53 sensitized glucose deprivation resistance through an intracellular reactive oxygen species (ROS) pathway and the induction of Bcl-2. Moreover, to understand whether pancreatic cancer cells with TG2 and p53 combined interference had possible effects on pancreatic β cells, we performed studies comparing pancreatic cancer cells with TG2 and p53 combined interference and pancreatic β cells. We discovered that the supernatant of pancreatic cancer cells withTG2 and p53 combined interference decreased cell survival in pancreatic β cells. Following the creation of an orthotopic pancreatic cancer mouse model, we revealed glucose tolerance abnormalities in the pancreatic cancer mouse model with TG2 and p53 combined interference, indicating a possible mechanism for damage of βcells in pancreatic cancer. Taken together, our findings establish roles for TG2 and p53 in response to glucose deprivation in pancreatic cancer cells. The relationship between TG2 and p53 suggests a possible mechanism for glucose tolerance abnormalities-associated pancreatic cancer and could have therapeutic potential for cancer treatment and diagnosis.
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影响因子：
4.3
作者：
Fischer, Nicholas W.;Prodeus, Aaron;Gariepy, Jean
通讯作者：
Gariepy, Jean
影响因子：
2.6
作者：
Hackeng WM;Hruban RH;Offerhaus GJ;Brosens LA
通讯作者：
Brosens LA
影响因子：
3.6
作者：
Illes, Dora;Terzin, Viktoria;Czako, Laszlo
通讯作者：
Czako, Laszlo
影响因子：
2.4
作者：
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通讯作者：
O'Reilly, Eileen M.
DOI：
10.1073/pnas.1501605112
发表时间：
2015-08-11
影响因子：
11.1
作者：
Daemen, Anneleen;Peterson, David;Evangelista, Marie
通讯作者：
Evangelista, Marie