title: Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis.
abstract: The intestinal epithelium has a high rate of turnover, and dysregulation of pathways that regulate regeneration can lead to tumor development; however, the negative regulators of oncogenic events in the intestinal epithelium are not fully understood. Here we identified a feedback loop between the epidermal growth factor receptor (EGFR), a known mediator of proliferation, and the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), in intestinal epithelial cells (IECs). We found that TRPV1 was expressed by IECs and was intrinsically activated upon EGFR stimulation. Subsequently, TRPV1 activation inhibited EGFR-induced epithelial cell proliferation via activation of Ca2+/calpain and resulting activation of protein tyrosine phosphatase 1B (PTP1B). In a murine model of multiple intestinal neoplasia (Apc(Min/+) mice), TRPV1 deficiency increased adenoma formation, and treatment of these animals with an EGFR kinase inhibitor reversed protumorigenic phenotypes, supporting a functional association between TRPV1 and EGFR signaling in IECs. Administration of a TRPV1 agonist suppressed intestinal tumorigenesis in Apc(Min/+) mice, similar to--as well as in conjunction with--a cyclooxygenase-2 (COX-2) inhibitor, which suggests that targeting both TRPV1 and COX-2 has potential as a therapeutic approach for tumor prevention. Our findings implicate TRPV1 as a regulator of growth factor signaling in the intestinal epithelium through activation of PTP1B and subsequent suppression of intestinal tumorigenesis.
authors.forename: Petrus R
authors.initials: PR
authors.lastname: de Jong
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Harris
authors.forename: Jihyung
authors.initials: J
authors.lastname: Lee
authors.forename: Samuel
authors.initials: S
authors.lastname: Bertin
authors.forename: James
authors.initials: J
authors.lastname: Jeffries
authors.forename: Michael
authors.initials: M
authors.lastname: Jung
authors.forename: Jen
authors.initials: J
authors.lastname: Duong
authors.forename: Amy I
authors.initials: AI
authors.lastname: Triano
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.forename: Yaron
authors.initials: Y
authors.lastname: Niv
authors.forename: David S
authors.initials: DS
authors.lastname: Herdman
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Chang-Whan
authors.initials: CW
authors.lastname: Kim
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D002154:Calpain / Q000502:physiology; D049109:Cell Proliferation; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D007414:Intestinal Neoplasms / Q000517:prevention & control*; D051379:Mice; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D052246:Cyclooxygenase 2 Inhibitors; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D066246:ErbB Receptors; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D002154:Calpain; D002118:Calcium
references.citation: Dev Dyn. 2006 Jun;235(6):1563-70
references.pmid: 16538672
references.citation: J Clin Invest. 2013 Aug;123(8):3459-71
references.pmid: 23867504
references.citation: Trends Biochem Sci. 2010 Aug;35(8):442-9
references.pmid: 20381358
references.citation: J Biol Chem. 2012 May 25;287(22):18182-9
references.pmid: 22496368
references.citation: J Biol Chem. 2004 Nov 5;279(45):47050-6
references.pmid: 15345710
references.citation: J Biol Chem. 2007 May 4;282(18):13303-15
references.pmid: 17339316
references.citation: J Clin Invest. 2007 Aug;117(8):2260-7
references.pmid: 17671655
references.citation: Cell Calcium. 2011 Sep;50(3):295-302
references.pmid: 21628069
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1521-6
references.pmid: 11818567
references.citation: Nature. 2011 Jun 15;474(7351):318-26
references.pmid: 21677748
references.citation: Cancer Res. 2009 Feb 1;69(3):905-13
references.pmid: 19155296
references.citation: Cell. 2010 Apr 16;141(2):331-43
references.pmid: 20403327
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20097-102
references.pmid: 19897733
references.citation: Nature. 2009 May 14;459(7244):262-5
references.pmid: 19329995
references.citation: Cancer Res. 2006 Jul 15;66(14):7370-7
references.pmid: 16849589
references.citation: Exp Cell Res. 2009 Feb 15;315(4):583-601
references.pmid: 19041864
references.citation: Cell Metab. 2012 Mar 7;15(3):292-7
references.pmid: 22405067
references.citation: Genetics. 2002 May;161(1):183-93
references.pmid: 12019233
references.citation: Cell. 2013 Apr 11;153(2):413-25
references.pmid: 23582329
references.citation: Nat Genet. 2007 Mar;39(3):338-46
references.pmid: 17259984
references.citation: J Physiol. 2011 Apr 1;589(Pt 7):1535-42
references.pmid: 21041532
references.citation: Cell. 2012 Mar 30;149(1):146-58
references.pmid: 22464327
references.citation: Pharmacol Ther. 2011 Jul;131(1):142-70
references.pmid: 21420431
references.citation: Adv Exp Med Biol. 2011;704:929-45
references.pmid: 21290334
references.citation: Pharmacol Rev. 2010 Sep;62(3):381-404
references.pmid: 20716668
references.citation: Nat Cell Biol. 2010 Mar;12(3):267-72
references.pmid: 20118922
references.citation: Development. 2005 Jan;132(2):279-89
references.pmid: 15590741
references.citation: N Engl J Med. 2006 Aug 31;355(9):873-84
references.pmid: 16943400
references.citation: Nat Rev Mol Cell Biol. 2011 Feb;12(2):104-17
references.pmid: 21252999
references.citation: FEBS J. 2010 Jan;277(2):327-42
references.pmid: 19951361
references.citation: J Cell Sci. 2011 Jun 1;124(Pt 11):1785-93
references.pmid: 21576352
references.citation: Am J Physiol Gastrointest Liver Physiol. 2003 Jul;285(1):G78-85
references.pmid: 12620887
references.citation: J Biol Chem. 2012 May 11;287(20):16146-57
references.pmid: 22451676
references.citation: Nature. 2012 Apr 15;484(7395):546-9
references.pmid: 22504183
references.citation: Nature. 1997 Oct 23;389(6653):816-24
references.pmid: 9349813
references.citation: Nat Med. 2002 Mar;8(3):289-93
references.pmid: 11875501
references.citation: Annu Rev Physiol. 2009;71:241-60
references.pmid: 18808327
references.citation: Nature. 2001 Jun 21;411(6840):957-62
references.pmid: 11418861
references.citation: Cancer Res. 2005 Nov 1;65(21):10088-95
references.pmid: 16267035
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G424-32
references.pmid: 19074643
references.citation: Biochem J. 1997 Oct 1;327 ( Pt 1):139-45
references.pmid: 9355745
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13396-401
references.pmid: 11606761
references.citation: Nat Med. 2010 Jun;16(6):665-70
references.pmid: 20473309
references.citation: Cell Calcium. 2007 Jul;42(1):17-25
references.pmid: 17184838
references.citation: Nat Genet. 2004 Oct;36(10):1117-21
references.pmid: 15378062
references.citation: Nature. 2007 Oct 25;449(7165):1003-7
references.pmid: 17934449
references.citation: Gastroenterology. 2011 Jan;140(1):275-85
references.pmid: 20888819
references.citation: Cancer Res. 2012 Apr 1;72(7):1705-16
references.pmid: 22396497
references.citation: Nature. 2003 Dec 4;426(6966):517-24
references.pmid: 14654832
references.citation: Nature. 2011 Jan 20;469(7330):415-8
references.pmid: 21113151
references.citation: Science. 2002 Mar 1;295(5560):1708-11
references.pmid: 11872838
references.citation: J Neurogenet. 2010 Dec;24(4):216-33
references.pmid: 21067449
references.citation: Science. 2005 Mar 25;307(5717):1904-9
references.pmid: 15790842
references.citation: J Cell Sci. 2003 Oct 15;116(Pt 20):4169-79
references.pmid: 12953068
references.citation: Cell Metab. 2010 Aug 4;12(2):130-41
references.pmid: 20674858
references.citation: Dev Biol. 2011 Jul 1;355(1):152-62
references.pmid: 21545794
references.citation: Nature. 2012 Jul 18;487(7407):330-7
references.pmid: 22810696
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):6155-60
references.pmid: 10823958
references.citation: Biochim Biophys Acta. 2010 Mar;1804(3):613-9
references.pmid: 19782770
references.citation: J Cell Biol. 2008 Mar 10;180(5):957-71
references.pmid: 18332219
references.citation: Nat Methods. 2008 Apr;5(4):299-302
references.pmid: 18327266
references.citation: Science. 2000 Apr 14;288(5464):306-13
references.pmid: 10764638
references.citation: Trends Cell Biol. 2001 Jun;11(6):258-66
references.pmid: 11356362
references.citation: Neuron. 2013 Feb 20;77(4):667-79
references.pmid: 23439120
references.citation: Nat Rev Immunol. 2010 Feb;10(2):131-44
references.pmid: 20098461
references.citation: Science. 2002 Jun 14;296(5575):2046-9
references.pmid: 12016205
references.citation: J Biol Chem. 1999 Mar 26;274(13):8958-65
references.pmid: 10085141
references.citation: Science. 2003 May 23;300(5623):1284-8
references.pmid: 12764195
references.citation: Cancer Res. 2006 Feb 15;66(4):2385-90
references.pmid: 16489045
references.citation: J Biol Chem. 2003 Jan 10;278(2):739-44
references.pmid: 12424235
references.citation: Pflugers Arch. 2007 Oct;455(1):157-68
references.pmid: 17479281
references.citation: N Engl J Med. 2009 Dec 17;361(25):2449-60
references.pmid: 20018966
references.citation: Cell. 2013 Jan 17;152(1-2):25-38
references.pmid: 23273993
references.citation: Science. 2004 Mar 12;303(5664):1684-6
references.pmid: 15017003
references.citation: Nat Cell Biol. 2012 Mar 04;14(4):401-8
references.pmid: 22388892
references.citation: Cancer Cell. 2007 Mar;11(3):214-6
references.pmid: 17349579
references.citation: Cancer Res. 2007 Mar 15;67(6):2420-4
references.pmid: 17347513
references.citation: Can J Neurol Sci. 2009 Mar;36(2):234-41
references.pmid: 19378721
references.citation: Nat Struct Mol Biol. 2004 Aug;11(8):730-7
references.pmid: 15258570