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Amino Acids

, Volume 33, Issue 3, pp 469–476 | Cite as

Cellular thiol status-dependent inhibition of tumor cell growth via modulation of p27kip1 translocation and retinoblastoma protein phosphorylation by 1′-acetoxychavicol acetate

  • Y. Unahara
  • A. Kojima-Yuasa
  • M. Higashida
  • D. O. Kennedy
  • A. Murakami
  • H. Ohigashi
  • I. Matsui-Yuasa
Article

Summary.

1′-Acetoxychavicol acetate (ACA) has been shown to inhibit tumor cell growth, but there is limited information on its effects on cell signaling and the cell cycle control pathway. In this study, we sought to determine how ACA alters cell cycle and its related control factors in its growth inhibitory effect in Ehrlich ascites tumor cells (EATC). ACA caused an accumulation of cells in the G1 phase and an inhibition of DNA synthesis, which were reversed by supplementation with N-acetylcysteine (NAC) or glutathione ethyl ester (GEE). Furthermore, ACA decreased hyperphosphorylated Rb levels and increased hypophosphorylated Rb levels. NAC and GEE also abolished the decease in Rb phosphorylation by ACA. As Rb phosphorylation is regulated by G1 cyclin dependent kinase and CDK inhibitor p27kip1, which is an important regulator of the mammalian cell cycle, we estimated the amount of p27kip1 levels by western blotting. Treatment with ACA had virtually no effect on the amount of p27kip1 levels, but caused a decrease in phosphorylated p27kip1 and an increase in unphosphorylated p27kip1 as well as an increase in the nuclear localization of p27kip1. These events were abolished in the presence of NAC or GEE. These results suggest that in EATC, cell growth inhibition elicited by ACA involves decreases in Rb and p27kip1 phosphorylation and an increase in nuclear localization of p27kip1, and these events are dependent on the cellular thiol status.

Keywords: ACA – Tumor cell growth – Rb – p27kip1 – Glutathione – Cell cycle 

Abbreviations:

pRb

hyperphosphorylated Retinoblastoma gene product

Rb

hypophosphorylated Rb

p27kip1

CDK inhibitor p27kip1

EATC

Ehrlich ascites tumor cells

NAC

N-acetylcysteine

GEE

glutathione ethyl ester

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Y. Unahara
    • 1
  • A. Kojima-Yuasa
    • 1
  • M. Higashida
    • 1
  • D. O. Kennedy
    • 2
  • A. Murakami
    • 3
  • H. Ohigashi
    • 3
  • I. Matsui-Yuasa
    • 1
  1. 1.Department of Food and Human Health Sciences, Graduate School of Human Life ScienceOsaka City UniversityOsakaJapan
  2. 2.Department of Environmental Health Sciences, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  3. 3.Division of Applied Life Sciences, Graduate School of AgricultureKyoto UniversityKyotoJapan

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