Cytotoxicity of lipid-soluble ginseng extracts is attenuated by plasma membrane redox enzyme NQO1 through maintaining redox homeostasis and delaying apoptosis in human neuroblastoma cells

Abstract

Lipid-soluble ginseng extracts (LSGE) is known to inhibit many types of cancer cells through arresting cell cycle and inducing apoptosis. Usually, normal cells are can also be damaged by anti-tumor reagents. The plasma membrane redox system (PMRS) is enhanced to compensate mitochondrial dysfunction and impaired energy metabolism. NADH-quinone oxidoreductase 1 (NQO1), a plasma membrane redox enzyme, is known to be induced by panaxytriol, one of components of lipid-soluble ginseng extracts (LSGE). The objective of this study was determine the mechanisms of NQO1 involved in neuroprotection in response to cytotoxicity induced by LSGE. Exposure of control SH-SY5Y cells to LSGE resulted in dramatic loss of cell viability in a dose-dependent manner. The loss of cell viability was significantly recovered in cells transfected with NQO1. LSGE-induced cell death occurred through apoptosis such as cell shrinkage, chromatin condensation and cleavage of poly (ADP-ribose) polymerase. These apoptotic features were significantly attenuated by overexpression of NQO1. Levels of oxidative/nitrative damage were highly elevated by LSGE in a dose-dependent manner. However, these elevated levels were greatly reduced by overexpression of NQO1. In addition, overexpression of NQO1 attenuated the decrease in mitochondrial complex I activity caused by LSGE. Taken together, these findings suggest that overexpressed NQO1 can protect cells against LSGE-induced cytotoxicity through lowering oxidative/nitrative damage and delaying apoptosis, supporting that stimulation of NQO1 activity could be a therapeutic targets in neurodegeration.

Treatment of Neuroblastoma Cells with Inhibitors of Protein Disulfide Isomerase Upregulates NQO1 Activity

“…Interestingly, seven out of eight of these biological processes involve apoptosis and cell death, and all of these involve NQO1 as well. This is in agreement with earlier studies showing that PDI inhibition induces apoptosis pathways , and that NQO1 inhibits the induction of apoptosis. − A functional protein association network analysis of these 36 DEGs supported this finding by predicting a tight cluster of multiple interactions among several of the DEGs involved in the identified cell death processes, in particular NQO1, MYC, GDF15, and TXNIP (Figure S6). Upregulation of NQO1 via inhibition of PDI could potentially affect the redox homeostasis in the cell as well, but the GO classification analysis does not indicate involvement of the redox metabolism.…”

Endocrine-Independent Cytotoxicity of Bisphenol A Is Mediated by Increased Levels of Reactive Oxygen Species and Affects Cell Cycle Progression

“…Apart from oxidative stress, BPA can also induce mitochondrial dysfunction, 28 which also contributes to the enhanced effect of internal oxidation. 39,40 The results of this study (Figure 1) correspond to the effect of mitochondrial dysfunction, and so, we present further evidence here suggesting that BPA-induced internal oxidation may be linked with events affecting progression of cell cycle. DNA damage is one of these events 18 where excessive production of ROS exceeds the cell's antioxidant defense system and interferes with the cell cycle checkpoints.…”

Identification of NQO1 and ferrochelatase as interaction partners for neuroprotective N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides

“…With respect of neuroprotection, the NQO1 is of particular interest because this enzyme is directly implicated in the detoxication of xenobiotics and has broad‐spectrum antioxidant properties . NQO1 is a highly inducible enzyme that is regulated by the Keap1/Nrf2/ARE pathway that may exercise a selective “gatekeeping” role in regulating the proteasomal degradation of specific proteins by promoting p53 accumulation in an MDM2 and ubiquitin‐independent manner .…”