title: Urokinase-type Plasminogen Activator (uPA) is Inhibited with QLT0267 a Small Molecule Targeting Integrin-linked Kinase (ILK).
abstract: Urokinase-type plasminogen activator (uPA) is associated with cancer recurrence where the most evidence comes from studies in breast cancer. According to the European Organization for Research and Treatment of Cancer, uPA is considered one of the most prominent biomarkers for cancer recurrence and therefore new agents are needed to inhibit it. Whether uPA is also expressed in pediatric cancers is yet unknown. If it is then uPA inhibitors might also help children with recurrent cancers. In this study, we addressed whether the integrin-linked kinase inhibitor (ILK), QLT0267, could suppress uPA. We previously showed that uPA expression is maximally inhibited when both the Akt and MAP kinase pathways were blocked which we anticipated can be achieved via QLT0267. In MDA-MB-231 breast cancer cells, QLT0267 blocked signaling through Akt and MAP kinase with a correlative decrease in uPA protein and mRNA, which corresponded to an inhibition of c-Jun phosphorylation. Consistent with these findings, cellular invasion was inhibited with either QLT0267 or with small interfering RNA against ILK. We then questioned whether uPA was commonly expressed in childhood sarcomas and if QLT0267 might be effective in this setting. We determined for the first time that uPA was highly expressed in rhabdomyosarcomas (RMS), but not Ewings sarcomas by screening cell lines (n = 31) and patient samples (n = 200) using Affymetrix microarrays. In alveolar RMS (ARMS) cell lines, QLT0267 blocked cell signaling, uPA production, invasion and ultimately survival. We concluded that QLT0267 blocks the production of uPA providing a new target for the management of recurrent cancers.
authors: Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, BC Canada.
authors: Nancy Dos
authors: ND
authors: Santos
authors: Golareh
authors: G
authors: Habibi
authors: Michelle
authors: M
authors: Wang
authors: Jennifer H
authors: JH
authors: Law
authors: Heather N
authors: HN
authors: Andrews
authors: Daniel
authors: D
authors: Wei
authors: Timothy
authors: T
authors: Triche
authors: Shoukat
authors: S
authors: Dedhar
authors: Sandra E
authors: SE
authors: Dunn
keywords: breast cancer; integrin-linked kinase; recurrence; rhabdomyosarcoma; urokinase-type plasminogen activator
references: Nat Rev Mol Cell Biol. 2002 Dec;3(12):932-43
references: 12461559
references: Cancer Res. 2006 Jan 1;66(1):393-403
references: 16397254
references: Mol Cancer Ther. 2005 Aug;4(8):1146-56
references: 16093430
references: Thromb Haemost. 2004 Mar;91(3):450-6
references: 14983219
references: Cancer Res. 2001 Feb 15;61(4):1367-74
references: 11245436
references: EMBO J. 2001 May 1;20(9):2160-70
references: 11331582
references: Nat Rev Cancer. 2005 Jan;5(1):51-63
references: 15630415
references: J Clin Oncol. 2002 Jun 1;20(11):2672-9
references: 12039929
references: Cancer. 1988 Aug 1;62(3):531-3
references: 3134120
references: J Natl Cancer Inst. 2002 Jan 16;94(2):116-28
references: 11792750
references: Cancer Invest. 2000;18(3):223-41
references: 10754991
references: J Biol Chem. 2003 Jun 20;278(25):22374-8
references: 12686550
references: Cancer Invest. 2003 Apr;21(2):208-16
references: 12743986
references: Lancet. 1989 Oct 28;2(8670):1049
references: 2572788
references: Science. 2002 Jul 5;297(5578):63-4
references: 12098689
references: Int J Cancer. 1999 May 5;81(3):443-50
references: 10209960
references: EMBO J. 1992 Dec;11(12):4573-82
references: 1330539
references: Oncogene. 2001 Oct 25;20(48):7064-72
references: 11704830
references: Cancer Res. 2004 Jan 1;64(1):286-91
references: 14729636
references: Gynecol Oncol. 2005 Oct;99(1):50-7
references: 16023182
references: Thromb Haemost. 1999 May;81(5):767-74
references: 10365752
references: Oncogene. 2000 Nov 16;19(48):5444-52
references: 11114721
references: Nat Biotechnol. 1999 Nov;17(11):1134-6
references: 10545926
references: Nature. 1991 Dec 12;354(6353):494-6
references: 1749429
references: Mol Cell Biol. 1999 Nov;19(11):7420-7
references: 10523630
references: Nat Med. 2001 Jun;7(6):673-9
references: 11385503
references: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13264-9
references: 10557309
references: Cancer Res. 2000 Feb 1;60(3):636-43
references: 10676647
references: Int J Oncol. 1998 Apr;12(4):911-20
references: 9499455
references: J Biol Chem. 2005 Oct 28;280(43):36529-40
references: 16127174
references: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11211-6
references: 9736715
references: J Natl Cancer Inst. 2002 Apr 17;94(8):597-606
references: 11959893
references: Breast Cancer Res Treat. 2005 Nov;94(1):47-52
references: 16172791
references: Clin Chem. 2002 Aug;48(8):1194-7
references: 12142372
references: Neoplasia. 2002 May-Jun;4(3):204-17
references: 11988840
references: FASEB J. 2000 Jun;14(9):1147-58
references: 10834937
references: Oncologist. 1999;4(1):34-44
references: 10337369
references: Proc Natl Acad Sci U S A. 1990 Mar;87(6):2230-4
references: 2138329
references: Oncogene. 1999 Sep 20;18(38):5340-8
references: 10498887
references: Mol Carcinog. 2000 Jan;27(1):10-7
references: 10642432
references: Mol Cell Biol. 1992 Aug;12(8):3507-13
references: 1630458
references: Oncogene. 1999 Dec 23;18(56):8024-32
references: 10637513
references: Nat Genet. 1997 Dec;17(4):439-44
references: 9398846
references: Cancer Cell. 2005 Sep;8(3):197-209
references: 16169465
references: Mol Cancer Ther. 2005 Nov;4(11):1681-8
references: 16275989
references: Clin Cancer Res. 2006 Jul 15;12(14 Pt 2):4392s-4395s
references: 16857816
references: Carcinogenesis. 2006 Jun;27(6):1134-45
references: 16474180
references: Breast Dis. 2003;17:41-7
references: 15687676