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BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

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

Authors: Laia Trigueros-Motos, Sandra Pérez-Torras, F Javier Casado, Míriam Molina-Arcas, Marçal Pastor-Anglada

Published in: BMC Cancer | Issue 1/2012

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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.
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Literature
1.
Hernandez-Vargas H, Rodriguez-Pinilla SM, Julian-Tendero M, Sanchez-Rovira P, Cuevas C, Anton A, Rios MJ, Palacios J, Moreno-Bueno G: Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007, 102 (2): 157-172. 10.1007/s10549-006-9322-9.CrossRefPubMed
2.
Lopez-Guerra M, Trigueros-Motos L, Molina-Arcas M, Villamor N, Casado FJ, Montserrat E, Campo E, Colomer D, Pastor-Anglada M: Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells. Haematologica. 2008, 93 (12): 1843-1851. 10.3324/haematol.13186.CrossRefPubMed
3.
Kho PS, Wang Z, Zhuang L, Li Y, Chew JL, Ng HH, Liu ET, Yu Q: p53-regulated transcriptional program associated with genotoxic stress-induced apoptosis. J Biol Chem. 2004, 279 (20): 21183-21192. 10.1074/jbc.M311912200.CrossRefPubMed
4.
Molina-Arcas M, Moreno-Bueno G, Cano-Soldado P, Hernandez-Vargas H, Casado FJ, Palacios J, Pastor-Anglada M: Human equilibrative nucleoside transporter-1 (hENT1) is required for the transcriptomic response of the nucleoside-derived drug 5'-DFUR in breast cancer MCF7 cells. Biochem Pharmacol. 2006, 72 (12): 1646-1656. 10.1016/j.bcp.2006.07.036.CrossRefPubMed
5.
Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, Engel A, Nielsen S: Aquaporin water channels–from atomic structure to clinical medicine. J Physiol. 2002, 542 (Pt 1): 3-16.CrossRefPubMedPubMedCentral
6.
7.
Ishibashi K, Kondo S, Hara S, Morishita Y: The evolutionary aspects of aquaporin family. Am J Physiol Regul Integr Comp Physiol. 2011, 300 (3): R566-R576. 10.1152/ajpregu.90464.2008.CrossRefPubMed
8.
9.
Saadoun S, Papadopoulos MC, Hara-Chikuma M, Verkman AS: Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature. 2005, 434 (7034): 786-792. 10.1038/nature03460.CrossRefPubMed
10.
Hu J, Verkman AS: Increased migration and metastatic potential of tumor cells expressing aquaporin water channels. FASEB J. 2006, 20 (11): 1892-1894. 10.1096/fj.06-5930fje.CrossRefPubMed
11.
Hara-Chikuma M, Verkman AS: Prevention of skin tumorigenesis and impairment of epidermal cell proliferation by targeted aquaporin-3 gene disruption. Mol Cell Biol. 2008, 28 (1): 326-332. 10.1128/MCB.01482-07.CrossRefPubMed
12.
Markert JM, Fuller CM, Gillespie GY, Bubien JK, McLean LA, Hong RL, Lee K, Gullans SR, Mapstone TB, Benos DJ: Differential gene expression profiling in human brain tumors. Physiol Genomics. 2001, 5 (1): 21-33.PubMed
13.
Moon C, Soria JC, Jang SJ, Lee J, Obaidul Hoque M, Sibony M, Trink B, Chang YS, Sidransky D, Mao L: Involvement of aquaporins in colorectal carcinogenesis. Oncogene. 2003, 22 (43): 6699-6703. 10.1038/sj.onc.1206762.CrossRefPubMed
14.
Shen L, Zhu Z, Huang Y, Shu Y, Sun M, Xu H, Zhang G, Guo R, Wei W, Wu W: Expression profile of multiple aquaporins in human gastric carcinoma and its clinical significance. Biomed Pharmacother. 2010, 64 (5): 313-318. 10.1016/j.biopha.2009.12.003.CrossRefPubMed
15.
Melis M, Hernandez J, Siegel EM, McLoughlin JM, Ly QP, Nair RM, Lewis JM, Jensen EH, Alvarado MD, Coppola D, et al: Gene expression profiling of colorectal mucinous adenocarcinomas. Dis Colon Rectum. 2010, 53 (6): 936-943. 10.1007/DCR.0b013e3181d320c4.CrossRefPubMed
16.
Villanueva A, Garcia C, Paules AB, Vicente M, Megias M, Reyes G, de Villalonga P, Agell N, Lluis F, Bachs O, et al: Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene. 1998, 17 (15): 1969-1978. 10.1038/sj.onc.1202118.CrossRefPubMed
17.
Cano-Soldado P, Molina-Arcas M, Alguero B, Larrayoz I, Lostao MP, Grandas A, Casado FJ, Pastor-Anglada M: Compensatory effects of the human nucleoside transporters on the response to nucleoside-derived drugs in breast cancer MCF7 cells. Biochem Pharmacol. 2008, 75 (3): 639-648. 10.1016/j.bcp.2007.10.005.CrossRefPubMed
18.
Zelenina M, Tritto S, Bondar AA, Zelenin S, Aperia A: Copper inhibits the water and glycerol permeability of aquaporin-3. J Biol Chem. 2004, 279 (50): 51939-51943. 10.1074/jbc.M407645200.CrossRefPubMed
19.
Ji C, Cao C, Lu S, Kivlin R, Amaral A, Kouttab N, Yang H, Chu W, Bi Z, Di W, et al: Curcumin attenuates EGF-induced AQP3 up-regulation and cell migration in human ovarian cancer cells. Cancer Chemother Pharmacol. 2008, 62 (5): 857-865. 10.1007/s00280-007-0674-6.CrossRefPubMed
20.
Kawamoto K: Flow cytometric analysis of cell cycle for the action mechanism of antineoplastic agents. Hum Cell. 1995, 8 (3): 85-88.PubMed
21.
Mobasheri A, Wray S, Marples D: Distribution of AQP2 and AQP3 water channels in human tissue microarrays. J Mol Histol. 2005, 36 (1–2): 1-14.CrossRefPubMed
22.
Kwon TH, Nielsen J, Masilamani S, Hager H, Knepper MA, Frokiaer J, Nielsen S: Regulation of collecting duct AQP3 expression: response to mineralocorticoid. Am J Physiol Renal Physiol. 2002, 283 (6): F1403-F1421.CrossRefPubMed
23.
Matsuzaki T, Suzuki T, Takata K: Hypertonicity-induced expression of aquaporin 3 in MDCK cells. Am J Physiol Cell Physiol. 2001, 281 (1): C55-C63.PubMed
24.
Nakakoshi M, Morishita Y, Usui K, Ohtsuki M, Ishibashi K: Identification of a keratinocarcinoma cell line expressing AQP3. Biol Cell. 2006, 98 (2): 95-100. 10.1042/BC20040127.CrossRefPubMed
25.
Delporte C, Chen ZJ, Baum BJ: Aquaporin 1 expression during the cell cycle in A5 cells. Biochem Biophys Res Commun. 1996, 228 (2): 223-228. 10.1006/bbrc.1996.1645.CrossRefPubMed
26.
Hara M, Verkman AS: Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice. Proc Natl Acad Sci U S A. 2003, 100 (12): 7360-7365. 10.1073/pnas.1230416100.CrossRefPubMedPubMedCentral
27.
Hara-Chikuma M, Verkman AS: Aquaporin-3 facilitates epidermal cell migration and proliferation during wound healing. J Mol Med. 2008, 86 (2): 221-231. 10.1007/s00109-007-0272-4.CrossRefPubMed
28.
Lewis W, Dalakas MC: Mitochondrial toxicity of antiviral drugs. Nat Med. 1995, 1 (5): 417-422. 10.1038/nm0595-417.CrossRefPubMed
29.
Petit F, Fromenty B, Owen A, Estaquier J: Mitochondria are sensors for HIV drugs. Trends Pharmacol Sci. 2005, 26 (5): 258-264. 10.1016/j.tips.2005.03.006.CrossRefPubMed
30.
Yeo TK, Kintner J, Armand R, Perez R, Lewis LD: Sublethal concentrations of gemcitabine (2',2'-difluorodeoxycytidine) alter mitochondrial ultrastructure and function without reducing mitochondrial DNA content in BxPC-3 human pancreatic carcinoma cells. Hum Exp Toxicol. 2007, 26 (12): 911-921. 10.1177/0960327107086513.CrossRefPubMed
31.
Fowler JD, Brown JA, Johnson KA, Suo Z: Kinetic investigation of the inhibitory effect of gemcitabine on DNA polymerization catalyzed by human mitochondrial DNA polymerase. J Biol Chem. 2008, 283 (22): 15339-15348. 10.1074/jbc.M800310200.CrossRefPubMedPubMedCentral
32.
Pastor-Anglada M, Felipe A, Casado FJ: Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies. Trends Pharmacol Sci. 1998, 19 (10): 424-430. 10.1016/S0165-6147(98)01253-X.CrossRefPubMed
33.
Pastor-Anglada MC FJ: Nucleoside transport into cells: role of nucleoside transporters SLC28 and SLC29 in cancer chemotherapy. Deoxynucleoside Analogs in Cancer Therapy Totowa. 2007, New Jersey: Humana Press
34.
Zheng X, Chen X: Aquaporin 3, a glycerol and water transporter, is regulated by p73 of the p53 family. FEBS Lett. 2001, 489 (1): 4-7. 10.1016/S0014-5793(00)02437-6.CrossRefPubMed
35.
Lapi E, Di Agostino S, Donzelli S, Gal H, Domany E, Rechavi G, Pandolfi PP, Givol D, Strano S, Lu X, et al: PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol Cell. 2008, 32 (6): 803-814. 10.1016/j.molcel.2008.11.019.CrossRefPubMed
36.
Woo J, Lee J, Chae YK, Kim MS, Baek JH, Park JC, Park MJ, Smith IM, Trink B, Ratovitski E, et al: Overexpression of AQP5, a putative oncogene, promotes cell growth and transformation. Cancer Lett. 2008, 264 (1): 54-62. 10.1016/j.canlet.2008.01.029.CrossRefPubMedPubMedCentral
Metadata
Title
Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs
Authors
Laia Trigueros-Motos
Sandra Pérez-Torras
F Javier Casado
Míriam Molina-Arcas
Marçal Pastor-Anglada
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-434

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