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01.07.2008 | Original Article

Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells

verfasst von: Shinji Osada, Fumio Sakashita, Yosiki Hosono, Kenichi Nonaka, Yasuharu Tokuyama, Hidenori Tanaka, Yoshiyuki Sasaki, Hiroyuki Tomita, Shuji Komori, Satoshi Matsui, Takao Takahashi

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2008

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Abstract

Background

Cytotoxicity of Vitamin K3 (VK3) is indicated to have the same mechanism with oxidative stress (H₂O₂). In the present study, we analyzed the differences and/or similarities in the cellular responses to oxidative stress and VK3 to clarify the mechanism of growth inhibition.

Methods

Cell viability was determined by a test method with 3-[4, 5-dimethyl-thiazol]-2, 5-dephenyl tetrazolium bromide (MTT). Expressions of cellular proteins were evaluated by Western blot analysis.

Results

The IC50 was calculated to be 47.3 ± 4.1 μM for VK3 and 2.2 ± 1.2 μM for H₂O₂. By Western blot analysis, VK3 or H₂O₂ was shown to induce rapid phosphorylation of extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases (JNKs). H₂O₂-induced phosphorylation of ERK and JNK was almost complete inhibited by more than 100-μM genistein. VK3-induced JNK phosphorylation was blocked by 100-μM genistein, but ERK phosphorylation was not inhibited completely even if 400-μM genistein was used. H₂O₂-induced inhibition of cell proliferation was completely blocked by 400-μM genistein, but the VK3 effect was reduced 72.8 ± 5.4% by the same concentration of genistein. H₂O₂-induced JNK phosphorylation and ERK phosphorylation were inhibited by staurosporine, protein kinase C (PKC) inhibitor. VK3-induced JNK phosphorylation was also blocked, but ERK phosphorylation was not affected. Staurosporine had no effect on VK3- or H₂O₂-induced growth inhibition. Treatment with a non-thiol antioxidant agent, catalase, completely abrogated H₂O₂-induced JNK and ERK phosphorylation, but a thiol antioxidant, l-cystein, had no effect on phosphorylation of them. The VK3-induced JNK phosphorylation was inhibited by catalase, but not l-cystein. But ERK phosphorylation was not inhibited by catalase and was abrogated completely by the thiol antioxidant. Catalase, but not l-cystein, blocked H₂O₂-induced growth inhibition, and l-cystein, but not catalase, blocked VK3-induced effects on cell proliferation completely.

Conclusion

VK3-induced ERK phosphorylation occurs by a different mechanism from oxidative stress, and it might have an important role to induce growth inhibition.

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Titel: Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells
verfasst von: Shinji Osada
Fumio Sakashita
Yosiki Hosono
Kenichi Nonaka
Yasuharu Tokuyama
Hidenori Tanaka
Yoshiyuki Sasaki
Hiroyuki Tomita
Shuji Komori
Satoshi Matsui
Takao Takahashi
Publikationsdatum: 01.07.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2008
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0610-9

Springer Medizin

Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells