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Reactive oxygen species regulate urokinase plasminogen activator expression and cell invasion via mitogen-activated protein kinase pathways after treatment with hepatocyte growth factor in stomach cancer cells.

Lee KH, Kim SW, Kim JR - J. Exp. Clin. Cancer Res. (2009)

Bottom Line: We confirmed that Rac-1 regulated ROS production after activation of the AKT pathway with HGF.Exogenously added H2O2 promoted the expression of HGF, but not in a dose-dependent manner and also showed negative expression of HGF after co-treatment with H2O2 and HGF.We clarified the downstream pathways regulated by ROS after treatment with H2O2, which showed negative control between FRK and p38 kinase activities for uPA regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, Korea. lkhee@med.yu.ac.kr

ABSTRACT

Background: Reactive oxygen species (ROS) are closely associated with the intracellular signal cascade, thus strongly implicating involvement in tumor progression. However, the mechanism by which ROS are generated and how ROS target downstream molecules to trigger tumor metastasis is unclear. In this study, we investigated the underlying signal pathways in ROS-induced urokinase plasminogen activator (uPA) expression in the human gastric cancer cells, NUGC-3 and MKN-28.

Methods and results: Intracellular ROS, as determined using the fluorescent probe, 2'-7' dichlorofluorescein diacetate, decreased after treatment with hepatocyte growth factor (HGF). We confirmed that Rac-1 regulated ROS production after activation of the AKT pathway with HGF. Exogenously added H2O2 promoted the expression of HGF, but not in a dose-dependent manner and also showed negative expression of HGF after co-treatment with H2O2 and HGF. Treatment with NAC, an intracellular free radical scavenger, decreased the enhancement of uPA production and tumor invasion in both cells. We clarified the downstream pathways regulated by ROS after treatment with H2O2, which showed negative control between FRK and p38 kinase activities for uPA regulation.

Conclusion: HGF regulates Rac-1-induced ROS production through the Akt pathway and ROS regulates uPA production and invasion via MAP kinase, which provides novel insight into the mechanisms underlying the progression of gastric cancer.

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Effects of PD 98059 and/or SB 203580 on H2O2-induced ERK phosphorylation. Serum-starved cells were pretreated with PD 98059 (10 μM) and/or SB 203580 (1 and 5 μM) for 30 min and then treated with HGF (10 ng/ml) for 15 min. ERK activation was evaluated by Western blot analysis. Representative data from 3 independent experiments are shown.
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Figure 12: Effects of PD 98059 and/or SB 203580 on H2O2-induced ERK phosphorylation. Serum-starved cells were pretreated with PD 98059 (10 μM) and/or SB 203580 (1 and 5 μM) for 30 min and then treated with HGF (10 ng/ml) for 15 min. ERK activation was evaluated by Western blot analysis. Representative data from 3 independent experiments are shown.

Mentions: To investigate the possibility of an interaction between ERK and p38 activation in H2O2-mediated uPA expression, the effect of SB 203580 on ERK activation was measured. Pretreatment with SB 203580 increased ERK phosphorylation in the H2O2-treated cells. Co-treatment with PD 098058 and SB 203580 decreased ERK phosphorylation. These results suggested that H2O2-mediated uPA secretion and the augmentation of this activity were regulated by ERK activation, and p38 activation might indirectly affect H2O2-mediated uPA secretion. In other words, the increments of H2O2-mediated uPA secretion and its level of expression according to the treatment by SB 203580 were mediated through ERK activation (Figure 12).


Reactive oxygen species regulate urokinase plasminogen activator expression and cell invasion via mitogen-activated protein kinase pathways after treatment with hepatocyte growth factor in stomach cancer cells.

Lee KH, Kim SW, Kim JR - J. Exp. Clin. Cancer Res. (2009)

Effects of PD 98059 and/or SB 203580 on H2O2-induced ERK phosphorylation. Serum-starved cells were pretreated with PD 98059 (10 μM) and/or SB 203580 (1 and 5 μM) for 30 min and then treated with HGF (10 ng/ml) for 15 min. ERK activation was evaluated by Western blot analysis. Representative data from 3 independent experiments are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2698863&req=5

Figure 12: Effects of PD 98059 and/or SB 203580 on H2O2-induced ERK phosphorylation. Serum-starved cells were pretreated with PD 98059 (10 μM) and/or SB 203580 (1 and 5 μM) for 30 min and then treated with HGF (10 ng/ml) for 15 min. ERK activation was evaluated by Western blot analysis. Representative data from 3 independent experiments are shown.
Mentions: To investigate the possibility of an interaction between ERK and p38 activation in H2O2-mediated uPA expression, the effect of SB 203580 on ERK activation was measured. Pretreatment with SB 203580 increased ERK phosphorylation in the H2O2-treated cells. Co-treatment with PD 098058 and SB 203580 decreased ERK phosphorylation. These results suggested that H2O2-mediated uPA secretion and the augmentation of this activity were regulated by ERK activation, and p38 activation might indirectly affect H2O2-mediated uPA secretion. In other words, the increments of H2O2-mediated uPA secretion and its level of expression according to the treatment by SB 203580 were mediated through ERK activation (Figure 12).

Bottom Line: We confirmed that Rac-1 regulated ROS production after activation of the AKT pathway with HGF.Exogenously added H2O2 promoted the expression of HGF, but not in a dose-dependent manner and also showed negative expression of HGF after co-treatment with H2O2 and HGF.We clarified the downstream pathways regulated by ROS after treatment with H2O2, which showed negative control between FRK and p38 kinase activities for uPA regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, Korea. lkhee@med.yu.ac.kr

ABSTRACT

Background: Reactive oxygen species (ROS) are closely associated with the intracellular signal cascade, thus strongly implicating involvement in tumor progression. However, the mechanism by which ROS are generated and how ROS target downstream molecules to trigger tumor metastasis is unclear. In this study, we investigated the underlying signal pathways in ROS-induced urokinase plasminogen activator (uPA) expression in the human gastric cancer cells, NUGC-3 and MKN-28.

Methods and results: Intracellular ROS, as determined using the fluorescent probe, 2'-7' dichlorofluorescein diacetate, decreased after treatment with hepatocyte growth factor (HGF). We confirmed that Rac-1 regulated ROS production after activation of the AKT pathway with HGF. Exogenously added H2O2 promoted the expression of HGF, but not in a dose-dependent manner and also showed negative expression of HGF after co-treatment with H2O2 and HGF. Treatment with NAC, an intracellular free radical scavenger, decreased the enhancement of uPA production and tumor invasion in both cells. We clarified the downstream pathways regulated by ROS after treatment with H2O2, which showed negative control between FRK and p38 kinase activities for uPA regulation.

Conclusion: HGF regulates Rac-1-induced ROS production through the Akt pathway and ROS regulates uPA production and invasion via MAP kinase, which provides novel insight into the mechanisms underlying the progression of gastric cancer.

Show MeSH
Related in: MedlinePlus