Oncotarget

Research Papers:

Effect of p53 on pancreatic cancer-glucose tolerance abnormalities by regulating transglutaminase 2 in resistance to glucose metabolic stress

Xiao Su, Xiangyi He, Qiwen Ben, Weiyi Wang, Huan Song, Qiao Ye, Yi Zang, Weiguang Li, Ping Chen, Weiyan Yao and Yaozong Yuan _

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Oncotarget. 2017; 8:74299-74311. https://doi.org/10.18632/oncotarget.19402

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Abstract

Xiao Su1, Xiangyi He1, Qiwen Ben1, Weiyi Wang2, Huan Song1, Qiao Ye1, Yi Zang1, Weiguang Li1, Ping Chen1, Weiyan Yao1 and Yaozong Yuan1

1Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China

2Department of Gastroenterology, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai 200433, China

Correspondence to:

Yaozong Yuan, email: yyz28@medmail.com.cn

Keywords: transglutaminase2, p53 gene, glucose metabolic stress, diabetes-associated pancreatic cancer

Abbreviations: TG2: tissue transglutaminase2; PanCa: pancreatic ductal adenocarcinoma

Received: April 26, 2017    Accepted: June 19, 2017    Published: July 19, 2017

ABSTRACT

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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