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Functional inhibition of aquaporin-3 with a gold-based compound induces blockage of cell proliferation

Serna, Ana, Galan-Cobo, Ana, Rodrigues, Claudia, Sanchez-Gomar, Ismael, Toledo-Aral, Juan Jose, Moura, Teresa F., Casini, Angela, Soveral, Graca and Echevarria, Miriam 2014. Functional inhibition of aquaporin-3 with a gold-based compound induces blockage of cell proliferation. Journal of Cellular Physiology 229 (11) , pp. 1787-1801. 10.1002/jcp.24632

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Abstract

AQP3 has been correlated with higher transport of glycerol, increment of ATP content, and larger proliferation capacity. Recently, we described the gold(III) complex Auphen as a very selective and potent inhibitor of AQP3's glycerol permeability (Pgly). Here we evaluated Auphen effect on the proliferation of various mammalian cell lines differing in AQP3 expression level: no expression (PC12), moderate (NIH/3T3) or high (A431) endogenous expression, cells stably expressing AQP3 (PC12-AQP3), and human HEK293T cells transiently transfected (HEK-AQP3) for AQP3 expression. Proliferation was evaluated in the absence or presence of Auphen (5 μM) by counting number of viable cells and analyzing 5-bromo-2′-deoxyuridine (BrdU) incorporation. Auphen reduced ≈50% the proliferation in A431 and PC12-AQP3, ≈15% in HEK-AQP3 and had no effect in PC12-wt and NIH/3T3. Strong arrest in the S-G2/M phases of the cell cycle, supported by analysis of cyclins (A, B1, D1, E) levels, was observed in AQP3-expressing cells treated with Auphen. Flow-cytometry of propidium iodide incorporation and measurements of mitochondrial dehydrogenases activity confirmed absence of cytotoxic effect of the drug. Functional studies evidenced ≈50% inhibition of A431 Pgly by Auphen, showing that the compound’s antiproliferative effect correlates with its ability to inhibit AQP3 Pgly. Role of Cys-40 on AQP3 permeability blockage by Auphen was confirmed by analyzing the mutated protein (AQP3-Ser-40). Accordingly, cells transfected with mutated AQP3 gained resistance to the antiproliferative effect of Auphen. These results highlight an Auphen inhibitory effect on proliferation of cells expressing AQP3 and suggest a targeted therapeutic effect on carcinomas with large AQP3 expression.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Publisher: Wiley Blackwell
ISSN: 0162-0134
Date of First Compliant Deposit: 1 November 2016
Date of Acceptance: 24 March 2014
Last Modified: 04 Jun 2017 08:30
URI: http://orca.cf.ac.uk/id/eprint/79295

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