Open AccessDemonstration and biological significance of a gastrin‐P21‐activated kinase 1 feedback loop in colorectal cancer cells
Author(s) -
Huynh Nhi,
Liu Kevin H.,
Yim Mildred,
Shulkes Arthur,
Baldwin Graham S.,
He Hong
Publication year - 2014
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12048
Subject(s) - gastrin , colorectal cancer , cancer , kinase , cancer research , medicine , oncology , biology , microbiology and biotechnology , secretion
Gastrins, including amidated gastrin 17 and glycine‐extended gastrin 17 , are important growth factors in colorectal cancer ( CRC ). The p21‐activated kinase 1 ( PAK 1) plays key roles in cellular processes including proliferation, survival, and motility, and in cell transformation and tumor progression. PAK 1 expression increases with the progression of CRC , and knockdown of PAK 1 blocks CRC cell growth and metastasis both in vitro and in vivo. The aim of this study was to determine the interaction between PAK 1 and gastrins in CRC cells. PAK 1 expression and activation were assayed by W estern blots, and concentrations of gastrin mRNA and peptides by real‐time PCR and radioimmunoassay, respectively. Proliferation of CRC cells was measured by 3 H ‐thymidine incorporation, and vascular endothelial growth factor ( VEGF ) secretion was measured by ELISA . Gastrins activated PAK 1 via PI 3 K ‐dependent pathways. Activated PAK 1 in turn mediated gastrin‐stimulated activation of β ‐catenin and VEGF secretion in CRC cells, as knockdown of PAK 1 blocked stimulation of these cellular processes by gastrins. Downregulation of gastrin reduced the expression and activity of PAK 1, but in contrast there was a compensatory increase in gastrins either when PAK 1 was downregulated, or after treatment with a PAK inhibitor. Our results indicate that PAK 1 is required for the stimulation of CRC cells by gastrins, and suggest the existence of an inhibitory feedback loop by which PAK 1 downregulates gastrin production in CRC cells.