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

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.

SUBMITTER: Meng Q

PROVIDER: S-EPMC6290009 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Meng Qingcai Q Xu Jin J Liang Chen C Liu Jiang J Hua Jie J Zhang Yiyin Y Ni Quanxing Q Shi Si S Yu Xianjun X

Cell death & disease 20181211 12

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 o ...[more]

PMID: 30538220

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Project description:Rationale: Post-translational modifications have emerged as vital players in alterations to tumor metabolism, including amino acid metabolic reprogramming. Jumonji domain-containing protein 2B (JMJD2B) enhances colorectal cancer (CRC) cell survival upon glucose deficiency. In the present study, we hypothesized that JMJD2B affects tumor cell amino acid metabolism in CRC and consequently promotes survival of CRC cells upon glucose deprivation. Methods: Non-target metabolic profiling was used to evaluate the roles of JMJD2B in CRC cell metabolism under glucose starvation. The roles of amino acid alterations induced by JMJD2B on CRC cell survival were determined by cell viability, immunoblotting, and clonogenic assays, and flow cytometry. The underlying mechanisms by which JMJD2B affected CRC cell metabolism were assessed using immunofluorescence staining, chromatin immunoprecipitation assays, electron microscopy in CRC cell lines, and using xenograft models. The correlation between JMJD2B and LC3B expression in human CRC specimens was assessed using immunohistochemistry. Results: Profound metabolic reprogramming was detected in JMJD2B knockdown CRC cells under glucose deficiency, especially those involving amino acid metabolites. Silencing of JMJD2B reduced the levels of certain amino acids that were induced by glucose deficiency. Among these amino acids, asparagine (Asn), phenylalanine (Phe), and histidine (His) promoted CRC cell survival under glucose starvation when JMJD2B was knocked down. Mechanistically, downregulation of JMJD2B inhibited autophagy in CRC cells through epigenetic regulation of microtubule associated protein 1 light chain 3 beta (LC3B), and subsequently decreased intracellular amino acid (Asn, Phe, His) levels under glucose deprivation, thus suppressing the survival of CRC cells. Using a nude mouse xenograft model, we verified that inhibiting JMJD2B could decrease the levels of amino acids (Asn, Phe, His). In addition, the inhibitory effects of JMJD2B-knockdown on tumor growth and amino acids level were rescued by overexpression of LC3B. Furthermore, we observed that the high expression of LC3B was more likely detected in tissuses with high expression of JMJD2B (P < 0.001) in 60 human CRC tissues. Conclusion: These results indicated that JMJD2B sustained the intracellular amino acids derived from autophagy in CRC cells upon glucose deficiency, partly through epigenetic regulation of LC3B, thus driving the malignancy of CRC.

Dataset Information

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

Publications

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

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