RT Journal Article
SR Electronic
T1 PDEδ inhibition impedes the proliferation and survival of human colorectal cancer cell lines harboring oncogenic KRas
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 377259
DO 10.1101/377259
A1 Christian H. Klein
A1 Dina C. Truxius
A1 Holger A. Vogel
A1 Jana Harizanova
A1 Sandip Murarka
A1 Pablo Martín-Gago
A1 Philippe I. H. Bastiaens
YR 2018
UL http://biorxiv.org/content/early/2018/07/25/377259.abstract
AB Novelty and Impact The ‘undruggable’ KRas is a prevalent oncogene in CRC with poor prognosis. In hPDAC cells pharmacological targeting of PDEδ affects oncogenic KRas signaling, but it remained unclear whether this approach is transferable to other cancer cells. Here, we show that genetic and pharmacologic PDEδ inhibition also impedes the proliferation of oncogenic, but not wild-type KRas bearing CRC cells indicating that PDEδ inhibition is a specific tool for targeting growth of oncogenic KRas bearing CRC.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.AbbreviationsCRCcolorectal cancerPMplasma membraneGDIguanine nucleotide dissociation inhibitorRErecycling endosomehPDACshuman pancreatic ductal adenocarcinoma cellsshRNAshort hairpin RNARTCAreal-time cell analysis7-AAD7-Aminoactinomycin D