ABSTRACT
Ras proteins, most notably KRas, are prevalent oncogenes in human cancer. Plasma membrane localization and thereby signaling of KRas is regulated by the prenyl-binding protein PDEδ. Recently, we have reported the specific anti-proliferative effects of PDEδ inhibition in KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, we investigated the proliferative dependence on the solubilizing activity of PDEδ of human colorectal cancer (CRC) cell lines with or without oncogenic KRas mutations. Our results show that genetic and pharmacologic interference with PDEδ specifically inhibits proliferation and survival of CRC cell lines harboring oncogenic KRas mutations whereas isogenic cell lines in which the KRas oncogene has been removed, or cell lines with oncogenic BRaf mutations or EGFR overexpression are not dependent on PDEδ. Pharmacological PDEδ inhibition is therefore a possible new avenue to target oncogenic KRas bearing CRC.
Subject(s)
Benzimidazoles/pharmacology , Cell Proliferation/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/metabolism , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell Survival/drug effects , Cell Survival/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cyclic Nucleotide Phosphodiesterases, Type 6/genetics , Cyclic Nucleotide Phosphodiesterases, Type 6/metabolism , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , HT29 Cells , Humans , Mutation , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , RNA InterferenceABSTRACT
The prenyl-binding protein PDEδ is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEδ, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEδ with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEδ inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEδ knockdown in a set of human pancreatic cancer cell lines.