Proteomic Investigation of Glyceraldehyde-Derived Intracellular AGEs and Their Potential Influence on Pancreatic Ductal Cells.

Lakmini Senavirathna,Sheng Pan,Ru Chen,Cheng Ma

doi:10.3390/cells10051005

Abstract

Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular AGEs could stimulate cancer induction and facilitate cancer progression. We evaluated the toxic effect of glyceraldehyde-derived intracellular AGEs on normal and malignant pancreatic ductal cells by assessing the cell viability, toxicity, and oxidative stress, followed by proteomic analysis. Our functional studies showed that pancreatic cancer cells (PANC-1 and MIA PaCa-2) were more resistant to glyceraldehyde treatment compared to normal pancreatic ductal epithelial cells (HPDE), while cytotoxicity effects were observed in all cell types. Furthermore, using 13C isotopic labeled glyceraldehyde, the proteomic data revealed a dose-dependent increment of the number of glycation adducts in both these cell types. HPDE cells showed a higher number of intracellular AGEs compared to cancer cells. At a molecular level, the glycations in the lysine residues of proteins showed a concurrent increase with the concentration of the glyceraldehyde treatment, while the arginine glycations appeared to be less affected by the glyceraldehyde doses. Further pathway analysis of these glycated proteins suggested that the glycated proteins participate in important biological processes that are major hallmarks of cancer initiation and progression, including metabolic processes, immune response, oxidative stress, apoptosis, and S100 protein binding.

Highlights

Pancreatic cancer is the third leading cause of cancer deaths in the USA [1]
The bright field images of the HPDE cells indicated that the cell number was greatly reduced after the treatment (Figure 1A), and the cell viability of HPDE was lost by about 40% compared to the control with no treatment (Figure 1B)
Certain levels of reactive oxygen species can promote cell proliferation, in cancer [40]. These findings suggest that ROS and GRP78 are implicated in tumor progression, which is consistent with our results of PANC-1 and MiaPac-2, in which increased ROS and GRP78 expression promoted the cell survival and growth during the glyceraldehyde treatment

Summary

Introduction

Pancreatic cancer is the third leading cause of cancer deaths in the USA [1]. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, as its occurrence is more than 90%. There are several risk factors associated with development of pancreatic cancer, such as age, genetics, cigarette smoke, obesity, dietary factors and diabetes mellitus (DM) [2,3,4,5]. Most of the PDACs are metastasized to other tissues or organs at the time of diagnosis. Its prevention and early diagnosis become important. The only clinical blood biomarker approved by the United States Food and Drug Administration for pancreatic cancer is cancer antigen 19-9 (CA 19-9), which is mostly used for monitoring the disease course during treatment [2]

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Conclusion