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The Pharmaceutical Society of Korea (대한약학회)
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Constitutive Activation of $p70^{S6k}$ in Cancer Cells

  • Kwon, Hyoung-Keun (Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University) ;
  • Bae, Gyu-Un (Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University) ;
  • Yoon, Jong-Woo (Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University) ;
  • Kim, Yong-Kee (Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University) ;
  • Lee, Hoi-Young (Department of Pharmacology, College of Medicine, Konyang University) ;
  • Lee, Hyang-Woo (Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University) ;
  • Han, Jeung-Whan (Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University)
  • Published : 2002.10.01
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Abstract

The mitogen-stimulated serine/threonine kinase $p70^{S6k}$ plays an important role in the progression of cells from $G_0/G$_1$$ to S phase of the cell cycle by translational up-regulation of a family of mRNA transcripts family of mRNA transcripts which contain polypyrimidine tract at their 5 transcriptional start site. Here, we report that $p70^{S6k}$ was constitutively phosphorylated and activated to various degrees in serum-deprived AGS, A2058, HT-1376, MG63, MCF7, MDA-MB-435S, MDA-MB-231 and MB-157. Rapamycin treatment induced a significant dephosphorylation and inactivation of $p70^{S6k}$ in all cancer cell lines, while wortmannin, a specific inhibitor of PI3-K, caused a mild dephosphorylation of $p70^{S6k}$ in AGS, MDA-MB-435S and MB-157. In addition, SQ20006, methylxanthine phosphodiesterase inhibitor, reduced the phosphorylation of $p70^{S6k}$ in all cancer cells tested. Consistent with inhibitory effect of rapamycin on $p70^{S6k}$ activity, rapamycin inhibited [$^3H$]-thymidine incorporation and increased the number of cells at $G_{0}G_{1}$ phase. Furthermore, these inhibitory effects were accompanied by the decrease in growth of cancer cells. Taken together, the results indicate that the antiproliferative activity of rapamycin might be attributed to cell cycle arrest at $G_{0}G_{1}$ phase in human cancer cells through the inhibition of constitutively activated $p70^{S6k}$ of cancer cells and suggest $p70^{S6k}$ as a potential target for therapeutic strategies aimed at preventing or inhibiting tumor growth.

Keywords

References

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