Functional Inhibition of Aquaporin-3 With a Gold-Based Compound Induces Blockage of Cell Proliferation

Ana Serna, Ana Galán-Cobo, Claudia Rodrigues, Ismael Sánchez-Gomar, Juan José Toledo-Aral, Teresa F. Moura, Angela Casini, Graça Soveral, Miriam Echevarría

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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 (5μM) 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. J. Cell. Physiol. 229: 1787-1801, 2014.

Original languageEnglish
Pages (from-to)1787-1801
Number of pages15
JournalJournal of Cellular Physiology
Volume229
Issue number11
DOIs
StatePublished - Nov 2014
Externally publishedYes

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