GPx1 is involved in the induction of protective autophagy in pancreatic cancer cells in response to glucose deprivation

Qingcai Meng,Jin Xu,Yiyin Zhang,Jiang Liu,Xianjun Yu,Si Shi,Jie Hua,Chen Liang,Quanxing Ni

doi:10.1038/s41419-018-1244-z

Abstract

Given the dense stroma and poor vascularization, access to nutrients is limited in the microenvironment of pancreatic ductal adenocarcinoma (PDA). PDA cells can efficiently recycle various metabolic substrates through the activation of different rescuing pathways, including the autophagy pathway. However, the precise roles of autophagy in cancer metabolism are not yet fully understood. In the present study, we first monitored the effect of glucose deprivation on autophagy and on the expression of glutathione peroxidase-1 (GPx1) in PDA cells under the glucose-free environment. Glucose starvation induced progressive autophagy activation in PDA cells via the activation of ROS/AMPK signaling. GPx1 degradation caused by glucose deprivation led to further ROS-dependent autophagy activation. Both GPx1 overexpression and autophagy inhibition sensitized cells to starvation-induced cell death through the activation of caspase-dependent apoptosis. Moreover, GPx1 may regulate glycolysis inhibition in PDA cells under glucose-deprived conditions. In summary, this study increases our understanding of the role of GPx1 in the induction of protective autophagy in PDA cells under extreme glucose starvation and may provide new therapeutic targets or innovative therapies.

Highlights

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive and lethal malignancies worldwide, with a death rate nearly equal to its rate of incidence[1]
Reactive oxygen species (ROS) generation is related to metabolic stress associated with nutrient deprivation and we examined and observed that the reactive oxygen species (ROS) levels were higher in PDA cells upon glucose deprivation (Fig. 1g)
We demonstrated that glucose deprivation resulted in the phosphorylation of AMP-dependent protein kinase (AMPK) (P-AMPK) in MiaPaCa-2 and SW1990 cells (Fig. 1h)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive and lethal malignancies worldwide, with a death rate nearly equal to its rate of incidence[1]. As tumors increase in size, cancer cells are exposed to heterogeneous microenvironments, with some regions displaying a significant lack of critical metabolites, including oxygen, glucose, and other nutrients[3]. Glucose-deprived conditions, rather than hypoxic conditions, may be a pivotal contributing factor for the death of cancer cells in the tumor microenvironment[5]. In PDA, alterations in metabolic programs, including increased glycolysis, altered glutamine metabolism, and autophagy activation, may be important for the growth and survival of cancer cells under nutrient stress conditions[6,7]. Among these pathways, glycolysis is the main metabolic pathway in the majority of PDAs8.

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Conclusion