ERO1α promotes hypoxic tumor progression and is associated with poor prognosis in pancreatic cancer

Gupta, Nikhil; Park, Jung Eun; Tse, Wilford; Low, Jee Keem; Kon, Oi Lian; McCarthy, Neil E.; Sze, Siu Kwan

doi:10.18632/oncotarget.27235

Cited by 32 publications

(33 citation statements)

References 52 publications

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“…In this study, we revealed that ERO1L expression is significantly elevated by activation of UPR. Consistent with two previous reports 35 , 36 , we also found that ERO1L can be induced by hypoxia, which is known to induce ER stress. The UPR-dependent elevation of ERO1L might be a reflection of the global enhancement of the entire secretory apparatus in response to ER stress.…”

Section: Discussionsupporting

confidence: 93%

“…ERO1L plays versatile oncogenic functions in human cancers, including rapid cell proliferation, increased cell invasion, promotion of angiogenesis, and immune escape 16 , 36 , 37 . Using the CRISPR/Cas9 approach, Gupta et al showed that ERO1L KO significantly suppresses PDAC cell proliferation and colony-forming potential 35 . Similarly, we found that shRNA-mediated ERO1L knockdown inhibits cell viability and colony-forming ability of two PDAC cells.…”

Section: Discussionmentioning

confidence: 99%

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Endoplasmic Reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in Pancreatic Cancer

Zhang¹,

Yang²,

Lin³

et al. 2020

Theranostics

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Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify ERO1L as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo . Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18 F-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in Pancreatic Cancer

Zhang¹,

Yang²,

Lin³

et al. 2020

Theranostics

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“…Proteome turnover analysis can be used to study disease states such as cancer and their potential treatments ( 67 , 68 , 69 , 70 , 71 , 72 , 73 ). One such study published by the Wiita lab examined proteome turnover in MM1.S multiple myeloma cells ( 72 ).…”

Section: Dynamic Silac Approachesmentioning

confidence: 99%

Proteome Turnover in the Spotlight: Approaches, Applications, and Perspectives

Ross¹,

Langer²,

Jovanović³

2021

Molecular & Cellular Proteomics

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In all cells, proteins are continuously synthesized and degraded in order to maintain protein homeostasis and modify gene expression levels in response to stimuli. Collectively, the processes of protein synthesis and degradation are referred to as protein turnover. At steady state, protein turnover is constant to maintain protein homeostasis, but in dynamic responses, proteins change their rates of synthesis and degradation in order to adjust their proteomes to internal or external stimuli. Thus, probing the kinetics and dynamics of protein turnover lends insight into how cells regulate essential processes such as growth, differentiation, and stress response. Here we outline historical and current approaches to measuring the kinetics of protein turnover on a proteome-wide scale in both steady-state and dynamic systems, with an emphasis on metabolic tracing using stable-isotope-labeled amino acids. We highlight important considerations for designing proteome turnover experiments, key biological findings regarding the conserved principles of proteome turnover regulation, and future perspectives for both technological and biological investigation.

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“…This low availability of oxygen is a condition derived from the rapid growth and accumulation of cells within the tumour. Inside the malignant growing tissue, cells undergo an adaptation to hypoxia and are able to grow with a resultant expansion of the tumour (Gupta et al., 2019). Activated PSC that are included in the tumour mass will also be subjected to hypoxia.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic stellate cells exhibit adaptation to oxidative stress evoked by hypoxia

Estarás

Martínez-Morcillo

García

et al. 2020

Biology of the Cell

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Background information. Pancreatic stellate cells play a key role in the fibrosis that develops in diseases such as pancreatic cancer. In the growing tumour, a hypoxia condition develops under which cancer cells are able to proliferate. The growth of fibrotic tissue contributes to hypoxia. In this study, the effect of hypoxia (1% O 2) on pancreatic stellate cells physiology was investigated. Changes in intracellular free-Ca 2+ concentration, mitochondrial free-Ca 2+ concentration and mitochondrial membrane potential were studied by fluorescence techniques. The status of enzymes responsible for the cellular oxidative state was analyzed by quantitative reverse transcriptionpolymerase chain reaction, high-performance liquid chromatography, spectrophotometric and fluorimetric methods and by Western blotting analysis. Cell viability and proliferation were studied by crystal violet test, 5-bromo-2deoxyuridine cell proliferation test and Western blotting analysis. Finally, cell migration was studied employing the wound healing assay. Results. Hypoxia induced an increase in intracellular and mitochondrial free-Ca 2+ concentration, whereas mitochondrial membrane potential was decreased. An increase in mitochondrial reactive oxygen species production was observed. Additionally, an increase in the oxidation of proteins and lipids was detected. Moreover, cellular total antioxidant capacity was decreased. Increases in the expression of superoxide dismutase 1 and 2 were observed and superoxide dismutase activity was augmented. Hypoxia evoked a decrease in the oxidized/reduced glutathione ratio. An increase in the phosphorylation of nuclear factor erythroid 2-related factor and in expression of the antioxidant enzymes catalytic subunit of glutamate-cysteine ligase, catalase, NAD(P)H-quinone oxidoreductase 1 and heme oxygenase-1 were detected. The expression of cyclin A was decreased, whereas expression of cyclin D and the content of 5-bromo-2-deoxyuridine were increased. This was accompanied by an increase in cell viability. The phosphorylation state of c-Jun NH 2-terminal kinase was increased, whereas that of p44/42 and p38 was decreased. Finally, cells subjected to hypoxia maintained migration ability. Conclusions and Significance. Hypoxia creates pro-oxidant conditions in pancreatic stellate cells to which cells adapt and leads to increased viability and proliferation.

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ERO1α promotes hypoxic tumor progression and is associated with poor prognosis in pancreatic cancer

Cited by 32 publications

References 52 publications

Endoplasmic Reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in Pancreatic Cancer

Endoplasmic Reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in Pancreatic Cancer

Proteome Turnover in the Spotlight: Approaches, Applications, and Perspectives

Pancreatic stellate cells exhibit adaptation to oxidative stress evoked by hypoxia

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