Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine)

Oncogene. 2002 Mar 7;21(11):1727-38. doi: 10.1038/sj.onc.1205225.

Abstract

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a central role in activating the AGC subfamily of protein kinases. In particular, PDK1 plays an important role in the regulation of Akt/PKB survival pathway by phosphorylating Akt on Thr308. Here we show that UCN-01 (7-hydroxystaurosporine), a drug now in clinical trials and with a unique fingerprint pattern, induced dephosphorylation and inactivation of Akt, resulting in the turn-off of the survival signals and the induction of apoptosis. Further analysis revealed that UCN-01-mediated Akt inactivation was caused by inhibiting upstream Akt kinase PDK1 (IC50=33 nM) both in vitro and from cells, but not by suppressing Akt itself or phosphatidylinositide-3-OH kinase. UCN-01-induced PDK1 inhibition was also observed in in vivo murine and human tumor xenografts. Overexpression of active form of Akt diminished the cytotoxic effects of UCN-01, suggesting that UCN-01 may in part exert its cytotoxicity by inhibiting PDK1-Akt survival pathway. Because UCN-01 has already proved to have potent anti-tumor activity in vivo, PDK1-Akt survival pathway is a new, attractive target for cancer chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Alkaloids / pharmacology*
  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caspases / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Staurosporine / analogs & derivatives
  • Transplantation, Heterologous

Substances

  • Alkaloids
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • 7-hydroxystaurosporine
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • AKT1 protein, human
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspases
  • Staurosporine