title: Targeting MMP-9, uPAR, and cathepsin B inhibits invasion, migration and activates apoptosis in prostate cancer cells.
abstract: Prostate cancer is one of the most commonly diagnosed cancers and the second leading cause of cancer deaths in Americans. The high mortality rate is mainly attributed to the invasiveness and metastasis of advanced prostate cancer. Targeting the molecules involved in metastasis could be an effective mode of treatment for prostate cancer. In this study, the therapeutic potential of siRNA-mediated targeting of matrix metalloproteinase-9 (MMP-9), urokinase plasminogen activator receptor (uPAR), and cathepsin B (CB) in prostate cancer was carried out using single and bi-cistronic siRNA-expressing constructs. Downregulation of MMP-9, uPAR, and CB inhibited matrigel invasion, in vitro angiogenesis and wound-healing migration ability of PC3 and DU145 prostate cancer cell lines. In addition, the siRNA treatments induced apoptosis in the tumor cells as determined by TUNEL and DNA laddering assays. An attempt to elucidate the apoptotic pathway showed the involvement of FAS-mediated activation of caspases-8 and -7. Further, mice with orthotopic prostate tumors treated with siRNA-expressing vectors showed significant inhibition in tumor growth and migration. In conclusion, we report that the siRNA-mediated knockdown of MMP-9, uPAR, and CB inhibits invasiveness and migration of prostate cancer cells and leads to apoptosis both in vitro and in vivo.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL 61605, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Nalla
authors.forename: B
authors.initials: B
authors.lastname: Gorantla
authors.forename: C S
authors.initials: CS
authors.lastname: Gondi
authors.forename: S S
authors.initials: SS
authors.lastname: Lakka
authors.forename: J S
authors.initials: JS
authors.lastname: Rao
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D002401:Cathepsin B; D020780:Matrix Metalloproteinase 9
references.citation: Oncogene. 2002 Nov 14;21(52):8011-9
references.pmid: 12439751
references.citation: Oncogene. 2003 Sep 4;22(38):5967-75
references.pmid: 12955075
references.citation: Hum Pathol. 2000 May;31(5):578-83
references.pmid: 10836297
references.citation: Cancer Lett. 2009 Jan 18;273(2):266-72
references.pmid: 19004543
references.citation: J Clin Invest. 2005 Oct;115(10):2665-72
references.pmid: 16200200
references.citation: Semin Cancer Biol. 2000 Dec;10(6):415-33
references.pmid: 11170864
references.citation: Nat Rev Mol Cell Biol. 2002 Dec;3(12):932-43
references.pmid: 12461559
references.citation: Int J Oncol. 2005 Jan;26(1):113-9
references.pmid: 15586231
references.citation: J Cell Mol Med. 2009 Sep;13(9B):4034-41
references.pmid: 19017363
references.citation: Eur J Cancer. 2007 May;43(7):1214-24
references.pmid: 17379505
references.citation: J Biol Chem. 1994 Jun 17;269(24):16766-73
references.pmid: 8207000
references.citation: J Clin Oncol. 2005 May 20;23(15):3302-3
references.pmid: 15738529
references.citation: Eur J Cancer. 1999 Jan;35(1):138-44
references.pmid: 10211102
references.citation: Nat Cell Biol. 2000 Oct;2(10):737-44
references.pmid: 11025665
references.citation: Cancer Res. 2008 Nov 15;68(22):9147-56
references.pmid: 19010886
references.citation: Mol Pharmacol. 1999 Feb;55(2):216-22
references.pmid: 9927611
references.citation: Int J Oncol. 2007 Nov;31(5):1039-50
references.pmid: 17912429
references.citation: Oncogene. 2007 Dec 6;26(55):7675-83
references.pmid: 17599056
references.citation: Cancer Treat Rev. 2008 Apr;34(2):122-36
references.pmid: 18162327
references.citation: Cancer Metastasis Rev. 2006 Mar;25(1):9-34
references.pmid: 16680569
references.citation: Cancer Res. 2003 May 15;63(10):2454-61
references.pmid: 12750266
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5045-50
references.pmid: 9560225
references.citation: Acta Histochem. 2010;112(1):3-25
references.pmid: 19162308
references.citation: J Biol Chem. 2000 Dec 15;275(50):39435-43
references.pmid: 10993883
references.citation: Biochemistry (Mosc). 2003 Jul;68(7):711-7
references.pmid: 12946252
references.citation: Nat Rev Cancer. 2006 Oct;6(10):764-75
references.pmid: 16990854
references.citation: Biomol Eng. 2006 Mar;23(1):17-34
references.pmid: 16466964
references.citation: Oncogene. 2001 Jan 11;20(2):147-55
references.pmid: 11313944
references.citation: Thromb Haemost. 2005 Apr;93(4):676-81
references.pmid: 15841311
references.citation: Bull Cancer. 2005 May 1;92(5):425-7
references.pmid: 15932803
references.citation: Int J Cancer. 2007 Nov 15;121(10):2307-16
references.pmid: 17657740
references.citation: Nat Rev Cancer. 2003 Jul;3(7):489-501
references.pmid: 12835669
references.citation: Cell. 1995 May 19;81(4):505-12
references.pmid: 7538907
references.citation: Matrix Biol. 1998 Mar;16(9):575-84
references.pmid: 9569125
references.citation: J Biol Chem. 2005 Oct 28;280(43):36529-40
references.pmid: 16127174
references.citation: Cancer Res. 1993 Jan 1;53(1):165-9
references.pmid: 7677979
references.citation: J Cell Sci. 2004 Apr 1;117(Pt 9):1847-57
references.pmid: 15075244
references.citation: J Biol Chem. 1995 Apr 7;270(14):7795-8
references.pmid: 7536190
references.citation: J Biol Chem. 2008 Jan 18;283(3):1545-1552
references.pmid: 17991734
references.citation: Anal Biochem. 1994 May 1;218(2):314-9
references.pmid: 8074286
references.citation: Curr Pharm Des. 2004;10(1):39-49
references.pmid: 14754404
references.citation: Cancer Res. 2004 Aug 1;64(15):5311-21
references.pmid: 15289337
references.citation: Int J Cancer. 2004 May 20;110(1):125-33
references.pmid: 15054877
references.citation: Curr Med Chem. 2006;13(19):2309-27
references.pmid: 16918357
references.citation: Curr Urol Rep. 2005 May;6(3):210-6
references.pmid: 15869725
references.citation: Neuron Glia Biol. 2004 May;1(2):165-76
references.pmid: 16804563
references.citation: CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
references.pmid: 18287387
references.citation: Cancer Res. 2003 Apr 1;63(7):1684-95
references.pmid: 12670923
references.citation: Gene Ther. 2005 Apr;12(8):702-14
references.pmid: 15674398
references.citation: J Natl Cancer Inst. 2005 Sep 7;97(17):1248-53
references.pmid: 16145045
references.citation: Prostate. 2001 Dec 1;49(4):235-42
references.pmid: 11746269
references.citation: Nat Rev Cancer. 2002 Mar;2(3):161-74
references.pmid: 11990853
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3617-26
references.pmid: 18519796
references.citation: Science. 1998 Aug 28;281(5381):1312-6
references.pmid: 9721091
references.citation: Urology. 2005 Jun;65(6 Suppl):8-12
references.pmid: 15939077
references.citation: Cell Biol Int. 2004;28(5):403-10
references.pmid: 15193284
references.citation: J Natl Cancer Inst. 2002 Jan 2;94(1):17-25
references.pmid: 11773278
references.citation: Science. 2005 Jan 14;307(5707):269-73
references.pmid: 15653507
references.citation: Mol Cancer Ther. 2006 Dec;5(12):3197-208
references.pmid: 17172424
references.citation: Science. 1989 Jul 21;245(4915):301-5
references.pmid: 2787530
references.citation: Oncogene. 2004 Nov 4;23(52):8486-96
references.pmid: 15378018
references.citation: Cancer Res. 2002 Apr 15;62(8):2390-7
references.pmid: 11956102