Inhibition of PDK-1 activity causes a reduction in cell proliferation and survival

Curr Biol. 2000 Nov 16;10(22):1439-42. doi: 10.1016/s0960-9822(00)00801-0.

Abstract

3-Phosphoinositide-dependent kinase-1 (PDK-1) was identified by its ability to phosphorylate and activate protein kinase B (PKB) in vitro [1,2] and can phosphorylate and activate additional protein kinases in the AGC family in vitro [3-6]. Its role in vivo has, however, only begun to be addressed. We used antisense oligonucleotides directed against PDK-1 expression to explore the role of PDK-1 in human glioblastoma cells (U87-MG), which express a mutant PTEN allele. Reduction in PDK-1 levels resulted in inhibition of PKB activity, and a reduction in phosphorylation on Thr308 and Ser473 of PKB. p70 S6 kinase (p70(S6K)) activity was also reduced. Cell proliferation was dramatically inhibited following treatment with PDK-1 antisense oligonucleotides, due to a combination of decreased cell doubling and an increase in apoptosis. This is in contrast to direct inhibition of phosphoinositide 3-OH kinase (PI 3-kinase), which results in G1 arrest with no effect on apoptosis. This study confirms both PKB and p70(S6K) as in vivo substrates for PDK-1. The effect of acute PDK-1 loss on cell proliferation and survival suggests the involvement of PI 3-kinase dependent and independent signaling events, and implicates PDK-1 as a potential therapeutic target for human neoplasms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Apoptosis*
  • Cell Division
  • Cell Survival
  • HeLa Cells
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases / metabolism
  • Tumor Cells, Cultured

Substances

  • Proto-Oncogene Proteins
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases