Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/124515
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Type: Journal article
Title: Combined pharmacological administration of AQP1 ion channel blocker AqB011 and water channel blocker Bacopaside II amplifies inhibition of colon cancer cell migration
Author: De Ieso, M.L.
Pei, J.V.
Nourmohammadi, S.
Smith, E.
Chow, P.H.
Kourghi, M.
Hardingham, J.E.
Yool, A.J.
Citation: Scientific Reports, 2019; 9(1):12635-1-12635-17
Publisher: NATURE PUBLISHING GROUP
Issue Date: 2019
ISSN: 2045-2322
2045-2322
Statement of
Responsibility: 
Michael L. De Ieso, Jinxin V. Pei, Saeed Nourmohammadi, Eric Smith, Pak Hin Chow, Mohamad Kourghi, Jennifer E . Hardingham, Andrea J. Yool
Abstract: Aquaporin-1 (AQP1) has been proposed as a dual water and cation channel that when upregulated in cancers enhances cell migration rates; however, the mechanism remains unknown. Previous work identified AqB011 as an inhibitor of the gated human AQP1 cation conductance, and bacopaside II as a blocker of AQP1 water pores. In two colorectal adenocarcinoma cell lines, high levels of AQP1 transcript were confirmed in HT29, and low levels in SW480 cells, by quantitative PCR (polymerase chain reaction). Comparable differences in membrane AQP1 protein levels were demonstrated by immunofluorescence imaging. Migration rates were quantified using circular wound closure assays and live-cell tracking. AqB011 and bacopaside II, applied in combination, produced greater inhibitory effects on cell migration than did either agent alone. The high efficacy of AqB011 alone and in combination with bacopaside II in slowing HT29 cell motility correlated with abundant membrane localization of AQP1 protein. In SW480, neither agent alone was effective in blocking cell motility; however, combined application did cause inhibition of motility, consistent with low levels of membrane AQP1 expression. Bacopaside alone or combined with AqB011 also significantly impaired lamellipodial formation in both cell lines. Knockdown of AQP1 with siRNA (confirmed by quantitative PCR) reduced the effectiveness of the combined inhibitors, confirming AQP1 as a target of action. Invasiveness measured using transwell filters layered with extracellular matrix in both cell lines was inhibited by AqB011, with a greater potency in HT29 than SW480. A side effect of bacopaside II at high doses was a potentiation of invasiveness, that was reversed by AqB011. Results here are the first to demonstrate that combined block of the AQP1 ion channel and water pores is more potent in impairing motility across diverse classes of colon cancer cells than single agents alone.
Keywords: Cell Line, Tumor
Cell Membrane
Pseudopodia
Humans
Colonic Neoplasms
Neoplasm Invasiveness
Triterpenes
Saponins
RNA, Small Interfering
Wound Healing
Cell Movement
Cell Survival
Gene Expression Regulation, Neoplastic
Aquaporin 1
Gene Knockdown Techniques
Rights: © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI: 10.1038/s41598-019-49045-9
Grant ID: http://purl.org/au-research/grants/arc/DP16112724
Appears in Collections:Aurora harvest 4
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