title: Downregulation of HtrA1 promotes resistance to anoikis and peritoneal dissemination of ovarian cancer cells.
abstract: We previously identified serine protease HtrA1 as a downregulated gene in epithelial ovarian cancer (EOC), but the functional consequence of loss of HtrA1 in EOC remains largely unclear. Here, we report that loss of HtrA1 attenuates anoikis--a critical physiologic barrier for tumor metastasis. In response to loss of anchorage, HtrA1 expression was upregulated in SKOV3 cells, resulting in autocatalytic activation of HtrA1. Stable knockdown of HtrA1 in SKOV3 and TOV21G cells resulted in resistance to anoikis due to enhanced activation of epidermal growth factor receptor (EGFR)/AKT pathway. In suspended SKOV3 cells, enhanced expression of HtrA1 inhibited EGFR/AKT pathway, leading to increased cell death, whereas protease-inactive mutant HtrA1 failed to result in either the inhibition of EGFR/AKT pathway or increased cell death, suggesting the requirement of HtrA1 protease activity in regulating anoikis. Immunoprecipitation and immunofluorescence assays revealed that HtrA1 interacted with EGFR not only on the cell membrane but also in the nucleus. Most importantly, downregulation of HtrA1 significantly enhanced the peritoneal dissemination of SKOV3ip1 cells in nonobese diabetic/severe combined immunodeficient mice, with increased phospho-EGFR level in corresponding tumor nodules compared with that in xenografts originated from the control cells. Taken together, these data reveal for the first time a novel function of HtrA1 in promoting anoikis by attenuating activation of EGFR/AKT pathway that may contribute to its metastasis suppression capacity, thus providing a possible explanation for the aggressive nature of human ovarian tumors with downregulated HtrA1.
authors.affiliation: Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: He
authors.forename: Takayo
authors.initials: T
authors.lastname: Ota
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
mesh_terms: D000818:Animals; D023102:Anoikis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D066246:ErbB Receptors; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases
references.citation: J Surg Oncol. 2009 Jun 1;99(7):424-7
references.pmid: 19365809
references.citation: Nature. 2004 Aug 26;430(7003):1034-9
references.pmid: 15329723
references.citation: Mol Biol Cell. 2001 May;12(5):1519-27
references.pmid: 11359940
references.citation: Nature. 2004 Aug 26;430(7003):973-4
references.pmid: 15329701
references.citation: Oncogene. 2009 May 21;28(20):2074-86
references.pmid: 19377510
references.citation: Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8637-43
references.pmid: 16361548
references.citation: Cancer Lett. 2008 Dec 18;272(2):177-85
references.pmid: 18579285
references.citation: J Cell Biochem. 2008 Sep 1;105(1):81-8
references.pmid: 18452160
references.citation: Nat Cell Biol. 2001 Sep;3(9):802-8
references.pmid: 11533659
references.citation: Oncogene. 2004 Feb 26;23(8):1636-44
references.pmid: 14716297
references.citation: Pharmacogenomics. 2008 Aug;9(8):1069-77
references.pmid: 18681782
references.citation: Oncogene. 2002 Sep 26;21(43):6684-8
references.pmid: 12242667
references.citation: Cell. 1994 May 20;77(4):477-8
references.pmid: 8187171
references.citation: Cancer Cell. 2004 Jan;5(1):19-24
references.pmid: 14749123
references.citation: Nat Cell Biol. 2003 Aug;5(8):733-40
references.pmid: 12844146
references.citation: Cancer Res. 2006 Oct 1;66(19):9428-36
references.pmid: 17018597
references.citation: Apoptosis. 2002 Jun;7(3):247-60
references.pmid: 11997669
references.citation: Mol Carcinog. 2009 Jul;48(7):610-7
references.pmid: 19058255
references.citation: Clin Cancer Res. 2000 Jun;6(6):2482-91
references.pmid: 10873103
references.citation: J Cell Biochem. 2009 May 15;107(2):253-63
references.pmid: 19301262
references.citation: Exp Cell Res. 2005 Aug 15;308(2):241-53
references.pmid: 15921680
references.citation: J Cell Sci. 2000 Jun;113 ( Pt 12):2139-47
references.pmid: 10825287
references.citation: Biochim Biophys Acta. 2008 Jun;1783(6):1177-88
references.pmid: 18405669
references.citation: Anticancer Res. 2006 Sep-Oct;26(5A):3455-9
references.pmid: 17094466
references.citation: J Am Coll Surg. 2009 Apr;208(4):614-20
references.pmid: 19476798
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Int J Cancer. 2003 Nov 1;107(2):215-23
references.pmid: 12949797
references.citation: J Clin Invest. 2006 Jul;116(7):1994-2004
references.pmid: 16767218
references.citation: Cancer Res. 2001 Jun 15;61(12):4837-41
references.pmid: 11406560
references.citation: J Mol Med (Berl). 2006 Aug;84(8):671-81
references.pmid: 16607561
references.citation: J Cell Biochem. 2009 Jul 1;107(4):639-54
references.pmid: 19479902
references.citation: Lancet. 2007 May 19;369(9574):1742-57
references.pmid: 17512859
references.citation: Cancer Res. 1973 Dec;33(12):3181-8
references.pmid: 4760534
references.citation: Cell Death Differ. 2008 Sep;15(9):1408-16
references.pmid: 18551132
references.citation: Apoptosis. 2008 Apr;13(4):531-42
references.pmid: 18322799
references.citation: Cancer Res. 2009 Mar 1;69(5):1706-11
references.pmid: 19223547
references.citation: J Biol Chem. 1998 Dec 18;273(51):34406-12
references.pmid: 9852107
references.citation: Br J Cancer. 2006 Jan 30;94(2):184-8
references.pmid: 16434982
references.citation: Cancer Sci. 2008 Mar;99(3):543-52
references.pmid: 18201274
references.citation: Nat Med. 2004 Nov;10(11):1251-6
references.pmid: 15502842
references.citation: Biochem Pharmacol. 2008 Dec 1;76(11):1352-64
references.pmid: 18708031
references.citation: Cancer Res. 2004 Aug 15;64(16):5720-7
references.pmid: 15313912
references.citation: Cancer Cell. 2005 Nov;8(5):393-406
references.pmid: 16286247
references.citation: J Clin Oncol. 2004 Jul 15;22(14):2790-9
references.pmid: 15254046
references.citation: Biochem Soc Trans. 2007 Aug;35(Pt 4):669-71
references.pmid: 17635117
references.citation: J Clin Oncol. 2003 May 1;21(9):1775-81
references.pmid: 12721254
references.citation: Clin Cancer Res. 2009 Nov 1;15(21):6484-9
references.pmid: 19861462
references.citation: Curr Cancer Drug Targets. 2009 Jun;9(4):451-68
references.pmid: 19519315
references.citation: Cancer Sci. 2009 Mar;100(3):434-40
references.pmid: 19154415
references.citation: Int J Gynecol Cancer. 2004 Nov-Dec;14(6):1086-96
references.pmid: 15571614