The Group I Pak inhibitor Frax-1036 sensitizes 11q13-amplified ovarian cancer cells to the cytotoxic effects of Rottlerin

Small GTPases. 2017 Oct 2;8(4):193-198. doi: 10.1080/21541248.2016.1213089. Epub 2016 Jul 18.

Abstract

The p21-activated kinases (PAKs) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/β-catenin cascades. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including breast, ovary, prostate, and brain cancer. PAK1 genomic amplification at 11q13 is the most common mechanism of Pak1 hyperactivation, though Pak1 mRNA and/or protein may be overexpressed in the absence of gene amplification. In previous in vitro and in vivo studies we have shown that ovarian cancer cells with amplified/overexpressed Pak1 were significantly more sensitive to pharmacologic inhibition of Pak1 compared to cells without 11q13 amplification. In the present study we examined if additional signaling pathways might be targeted in tandem with the Group I Pak inhibitor Frax-1036 in ovarian cancer cells. Using the ICCB Known Bioactives Library, we found that the cytotoxic effect of Frax-1036 was significantly higher in combination with the PKCδ inhibitor, Rottlerin, suggesting that Pak inhibitors might be combined with other agents to treat 11q13-amplified ovarian cancer.

Keywords: chromosomal amplification; oncogene; ovarian cancer; p21 inactivated kinase; protein kinase; sensitized screen; signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetophenones / pharmacology*
  • Benzopyrans / pharmacology*
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 11 / genetics*
  • Drug Synergism
  • Female
  • Humans
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / pharmacology*
  • Pyrimidines / pharmacology*
  • Signal Transduction / drug effects
  • p21-Activated Kinases / antagonists & inhibitors*

Substances

  • Acetophenones
  • Benzopyrans
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrimidines
  • rottlerin
  • PAK1 protein, human
  • p21-Activated Kinases