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IQGAP1 Maintains Pancreatic Ductal Adenocarcinoma Clonogenic Growth and Metastasis
- Publication Year :
- 2019
-
Abstract
- Objectives IQ motif containing GTPase-activating protein 1 (IQGAP1) acts as a scaffold for aberrant mitogen-activated protein kinase (MAPK) signaling driven by KRAS mutations in pancreatic ductal adenocarcinoma (PDAC). We determined the role of IQGAP1 in clonogenic growth and metastasis in PDAC. Methods We inhibited IQGAP1 expression using shRNA and assessed clonogenic growth, cell migration, and MAPK signaling in vitro and tumor initiation and metastasis in vivo. The efficacy of a peptide mimicking the IQGAP1 WW domain that binds and inhibits ERK1/2 was determined in vitro and in vivo. Results IQGAP1 loss inhibited clonogenic growth and migration of KRAS-dependent PDAC cells by disrupting MAPK signaling. In mice, IQGAP1 knockdown decreased tumor-initiating cell frequency and metastasis. WW peptide treatment inhibited clonogenic growth and in vivo tumor growth. Conclusions Pancreatic ductal adenocarcinoma clonogenic growth, metastasis, and tumor initiation are dependent on MAPK signaling via IQGAP1. Treatment with a WW peptide disrupts IQGAP1 function and represents a novel targeting strategy for PDAC.
- Subjects :
- MAPK/ERK pathway
endocrine system diseases
MAP Kinase Signaling System
Endocrinology, Diabetes and Metabolism
Cell
Tumor initiation
Mice, SCID
Article
Metastasis
03 medical and health sciences
0302 clinical medicine
Endocrinology
IQGAP1
Cell Movement
Mice, Inbred NOD
Pancreatic cancer
Cell Line, Tumor
Internal Medicine
medicine
Animals
Humans
Neoplasm Metastasis
Clonogenic assay
Cell Proliferation
Mice, Knockout
Hepatology
Chemistry
Cell migration
medicine.disease
Xenograft Model Antitumor Assays
digestive system diseases
Pancreatic Neoplasms
medicine.anatomical_structure
RNAi Therapeutics
ras GTPase-Activating Proteins
030220 oncology & carcinogenesis
Cancer research
030211 gastroenterology & hepatology
RNA Interference
Carcinoma, Pancreatic Ductal
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....533ebcda3b9ec756445742ea45bf8329