title: Aquaporin-3 Controls Breast Cancer Cell Migration by Regulating Hydrogen Peroxide Transport and Its Downstream Cell Signaling.
abstract: Most breast cancer mortality is due to clinical relapse associated with metastasis. CXCL12/CXCR4-dependent cell migration is a critical process in breast cancer progression; however, its underlying mechanism remains to be elucidated. Here, we show that the water/glycerol channel protein aquaporin-3 (AQP3) is required for CXCL12/CXCR4-dependent breast cancer cell migration through a mechanism involving its hydrogen peroxide (H2O2) transport function. Extracellular H2O2, produced by CXCL12-activated membrane NADPH oxidase 2 (Nox2), was transported into breast cancer cells via AQP3. Transient H2O2 accumulation was observed around the membrane during CXCL12-induced migration, which may be facilitated by the association of AQP3 with Nox2. Intracellular H2O2 then oxidized PTEN and protein tyrosine phosphatase 1B (PTP1B) followed by activation of the Akt pathway. This contributed to directional cell migration. The expression level of AQP3 in breast cancer cells was related to their migration ability both in vitro and in vivo through CXCL12/CXCR4- or H2O2-dependent pathways. Coincidentally, spontaneous metastasis of orthotopic xenografts to the lung was reduced upon AQP3 knockdown. These findings underscore the importance of AQP3-transported H2O2 in CXCL12/CXCR4-dependent signaling and migration in breast cancer cells and suggest that AQP3 has potential as a therapeutic target for breast cancer.
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Satooka
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan haramari@kuhp.kyoto-u.ac.jp.
authors.forename: Mariko
authors.initials: M
authors.lastname: Hara-Chikuma
mesh_terms: D000818:Animals; D051400:Aquaporin 3 / Q000378:metabolism*; D001693:Biological Transport, Active; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010084:Oxidation-Reduction; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C496027:AQP3 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D051400:Aquaporin 3; D006861:Hydrogen Peroxide; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D051059:PTEN Phosphohydrolase
references.citation: J Biol Chem. 2012 Feb 10;287(7):4403-10
references.pmid: 22147704
references.citation: Nat Rev Immunol. 2012 Apr;12(4):253-68
references.pmid: 22437938
references.citation: Nat Rev Cancer. 2012 Sep;12(9):627-37
references.pmid: 22918415
references.citation: J Exp Med. 2012 Sep 24;209(10):1743-52
references.pmid: 22927550
references.citation: Am J Pathol. 2012 Dec;181(6):2047-57
references.pmid: 23041062
references.citation: Oncol Rep. 2013 Feb;29(2):535-40
references.pmid: 23165320
references.citation: Med Oncol. 2013;30(3):636
references.pmid: 23797770
references.citation: Chem Rev. 2013 Jul 10;113(7):4633-79
references.pmid: 23514336
references.citation: Nat Med. 2013 Nov;19(11):1423-37
references.pmid: 24202395
references.citation: Biomed Res Int. 2013;2013:206525
references.pmid: 24224160
references.citation: J Mammary Gland Biol Neoplasia. 2014 Mar;19(1):91-102
references.pmid: 24338153
references.citation: Nat Rev Drug Discov. 2014 Apr;13(4):259-77
references.pmid: 24625825
references.citation: J Exp Clin Cancer Res. 2014;33:38
references.pmid: 24887009
references.citation: Exp Physiol. 2014 Jul;99(7):974-84
references.pmid: 24803527
references.citation: Nat Commun. 2015;6:7454
references.pmid: 26100668
references.citation: Biochim Biophys Acta. 2015 Oct;1848(10 Pt B):2576-83
references.pmid: 25204262
references.citation: J Biol Chem. 2001 Jan 5;276(1):624-8
references.pmid: 11035042
references.citation: Nature. 2001 Mar 1;410(6824):50-6
references.pmid: 11242036
references.citation: J Biol Chem. 2002 Jun 7;277(23):20336-42
references.pmid: 11916965
references.citation: Br J Cancer. 2002 Dec 2;87(12):1404-10
references.pmid: 12454769
references.citation: Nature. 2003 Jun 12;423(6941):769-73
references.pmid: 12802338
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1886-91
references.pmid: 14762163
references.citation: Mol Cancer Res. 2004 Jun;2(6):327-38
references.pmid: 15235108
references.citation: J Biol Chem. 1994 Aug 26;269(34):21845-9
references.pmid: 8063828
references.citation: Science. 1995 Aug 4;269(5224):690-3
references.pmid: 7624799
references.citation: J Biol Chem. 1997 Jan 3;272(1):217-21
references.pmid: 8995250
references.citation: Nat Med. 1998 Jan;4(1):72-7
references.pmid: 9427609
references.citation: J Biol Chem. 1998 Jun 19;273(25):15366-72
references.pmid: 9624118
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13513-8
references.pmid: 9811831
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16419-24
references.pmid: 15534200
references.citation: Nature. 2005 Jul 28;436(7050):518-24
references.pmid: 16049480
references.citation: Nat Methods. 2006 Apr;3(4):281-6
references.pmid: 16554833
references.citation: Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):243-70
references.pmid: 16677071
references.citation: Science. 2006 Jun 30;312(5782):1882-3
references.pmid: 16809515
references.citation: Biochim Biophys Acta. 2006 Aug;1758(8):994-1003
references.pmid: 16566894
references.citation: Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1819-27
references.pmid: 16987034
references.citation: Biochem J. 2007 Jan 1;401(1):1-11
references.pmid: 17150040
references.citation: Cell. 2007 Jun 29;129(7):1261-74
references.pmid: 17604717
references.citation: Science. 2008 May 2;320(5876):661-4
references.pmid: 18388260
references.citation: J Mol Med (Berl). 2008 May;86(5):523-9
references.pmid: 18311471
references.citation: J Invest Dermatol. 2008 Sep;128(9):2145-51
references.pmid: 18548108
references.citation: Cancer Chemother Pharmacol. 2008 Oct;62(5):857-65
references.pmid: 18214481
references.citation: Immunity. 2008 Oct 17;29(4):551-64
references.pmid: 18957266
references.citation: Clin Cancer Res. 2010 Jun 1;16(11):2927-31
references.pmid: 20484021
references.citation: Antioxid Redox Signal. 2010 Aug 15;13(4):449-65
references.pmid: 20017602
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15681-6
references.pmid: 20724658
references.citation: Cancer Biol Ther. 2010 Jun 15;9(12):1000-7
references.pmid: 20364107
references.citation: Trends Immunol. 2010 Oct;31(10):370-6
references.pmid: 20829112
references.citation: Science. 2011 Mar 25;331(6024):1559-64
references.pmid: 21436443
references.citation: Cancer Sci. 2011 Jun;102(6):1128-36
references.pmid: 21401805
references.citation: Nat Chem Biol. 2011 Aug;7(8):504-11
references.pmid: 21769097
references.citation: Nat Rev Cancer. 2011 Aug;11(8):573-87
references.pmid: 21779009
references.citation: Cell. 2011 Oct 14;147(2):275-92
references.pmid: 22000009
references.citation: Nat Chem Biol. 2012 Jan;8(1):57-64
references.pmid: 22158416
references.citation: Trends Cell Biol. 2012 Feb;22(2):107-15
references.pmid: 22209517