Email updates

Keep up to date with the latest news and content from BMC Cancer and BioMed Central.

Open Access Research article

Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs

Laia Trigueros-Motos12, Sandra Pérez-Torras1, F Javier Casado1, Míriam Molina-Arcas13 and Marçal Pastor-Anglada1*

Author affiliations

1 Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, and Centro de Investigación Biomédica en Red – Enfermedades Hepáticas y Digestivas (CIBER EHD), Diagonal 645, 08028, Barcelona, Spain

2 Present address: Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

3 Present address: Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, UK

For all author emails, please log on.

Citation and License

BMC Cancer 2012, 12:434  doi:10.1186/1471-2407-12-434

Published: 27 September 2012

Abstract

Background

Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite 5-deoxy-5-fluorouridine (5-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA in cancer cells treated with 5-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3 participates in the activity of genotoxic agents.

Methods

The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches.

Results

5-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced.

Conclusions

Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest.