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Huynh N, Liu KH, Yim M, et al. Demonstration and biological significance of a gastrin-P21-activated kinase 1 feedback loop in colorectal cancer cells. Physiol Rep. 2014;2(6)doi: 10.14814/phy2.12048.
Huynh, N., Liu, K. H., Yim, M., Shulkes, A., Baldwin, G. S., & He, H. (2014). Demonstration and biological significance of a gastrin-P21-activated kinase 1 feedback loop in colorectal cancer cells. Physiological reports, 2(6), . https://doi.org/10.14814/phy2.12048
Huynh, Nhi, et al. "Demonstration and biological significance of a gastrin-P21-activated kinase 1 feedback loop in colorectal cancer cells." Physiological reports vol. 2,6 (2014). doi: https://doi.org/10.14814/phy2.12048
Huynh N, Liu KH, Yim M, Shulkes A, Baldwin GS, He H. Demonstration and biological significance of a gastrin-P21-activated kinase 1 feedback loop in colorectal cancer cells. Physiol Rep. 2014 Jun 24;2(6). doi: 10.14814/phy2.12048. Print 2014 Jun 01. PMID: 24963032; PMCID: PMC4208650.
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Physiol Rep. 2014 Jun 24;2(6). doi: 10.14814/phy2.12048. Print 2014 Jun 01.

Demonstration and biological significance of a gastrin-P21-activated kinase 1 feedback loop in colorectal cancer cells.

Physiological reports

Nhi Huynh, Kevin H Liu, Mildred Yim, Arthur Shulkes, Graham S Baldwin, Hong He

Affiliations

  1. Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.

PMID: 24963032 PMCID: PMC4208650 DOI: 10.14814/phy2.12048

Abstract

Gastrins, including amidated gastrin17 and glycine-extended gastrin17, are important growth factors in colorectal cancer (CRC). The p21-activated kinase 1 (PAK1) plays key roles in cellular processes including proliferation, survival, and motility, and in cell transformation and tumor progression. PAK1 expression increases with the progression of CRC, and knockdown of PAK1 blocks CRC cell growth and metastasis both in vitro and in vivo. The aim of this study was to determine the interaction between PAK1 and gastrins in CRC cells. PAK1 expression and activation were assayed by Western 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 PAK1 via PI3K-dependent pathways. Activated PAK1 in turn mediated gastrin-stimulated activation of β-catenin and VEGF secretion in CRC cells, as knockdown of PAK1 blocked stimulation of these cellular processes by gastrins. Downregulation of gastrin reduced the expression and activity of PAK1, but in contrast there was a compensatory increase in gastrins either when PAK1 was downregulated, or after treatment with a PAK inhibitor. Our results indicate that PAK1 is required for the stimulation of CRC cells by gastrins, and suggest the existence of an inhibitory feedback loop by which PAK1 downregulates gastrin production in CRC cells.

© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Keywords: Colon cancer; Gamide; glycine extended; p21‐activated kinase 1

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