[GIPC: a new target for therapy in pancreatic adenocarcinoma?].
GIPC is highly expressed in human pancreatic adenocarcinoma and is a central protein for the stability of IGF-1R in pancreatic adenocarcinoma cell lines (15). The goal of this study was to prove the importance of GIPC in vivo and to evaluate possible therapeutic strategies that target this protein and its PDZ domain. In vivo effects of GIPC knockout were studied after lentiviral transduction of luciferase-expressing MiaPaCa2 pancreatic cancer cells with shRNA against GIPC; growth characteristics were monitored with bioluminiscence. Knockdown of GIPC led to a significant inhibition of pancreatic tumor cell growth in vivo in different mouse models. To test a possible therapeutic approach, the PDZ domain of GIPC was targeted by a short peptide composed of the amino acid sequence PSQSSSEA. This octapeptide was designed based on the C-terminal binding motif of GAIP. Targeting GIPC with this peptide inhibited the association between IGF-1R and GIPC. The subsequent downregulation of IGF-1R decreased proliferation in vitro and in vivo. In conclusion, our findings suggest that targeting GIPC and its PDZ domain-mediated interaction with the tyrosine kinase receptor IGF-1R could be a promising new treatment option for pancreatic cancer.
Muders
M H
MH
Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, USA.
Baretton
G B
GB
Aust
D E
DE
Dutta
S K
SK
Wang
E
E
Ikeda
Y
Y
Spaller
M R
MR
Datta
K
K
Mukhopadhyay
D
D
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D017353:Gene Deletion; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C492009:GIPC1 protein, human; D009842:Oligopeptides; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering