Abstract
Since the NF-κB/relA transcription factor is constitutively activated in human prostate cancer cells, we determined whether blocking NF-κB/relA activity in human prostate cancer cells affected their angiogenesis, growth, and metastasis in an orthotopic nude mouse model. Highly metastatic PC-3M human prostate cancer cells were transfected with a mutated IκBα (IκBαM), which blocks NF-κB activity. Parental (PC-3M), control vector-transfected (PC-3M-Neo), and IκBαM-transfected (PC-3M–IκBαM) cells were injected into the prostate gland of nude mice. PC-3M and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastasis, whereas PC-3M–IκBαM cells produced slow growing tumors with low metastatic potential. NF-κB signaling blockade significantly inhibited in vitro and in vivo expression of three major proangiogenic molecules, VEGF, IL-8, and MMP-9, and hence decreased neoplastic angiogenesis. Inhibition of NF-κB activity in PC-3M cells also resulted in the downregulation of MMP-9 mRNA and collagenase activity, resulting in decreased invasion through Matrigel. Collectively, these data suggest that blockade of NF-κB activity in PC-3M cells inhibits angiogenesis, invasion, and metastasis.
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References
Abeyama K, Eng W, Jester JV, Vink AA, Edelbaum D, Cockerell CJ, Bergstresser PR, Takashima A . 2000 J. Clin. Invest. 12: 1751–1759
Balbay MD, Pettaway CA, Kuniyasu H, Inoue K, Ramirez E, Li E, Fidler IJ, Dinney CP . 1999 Cancer Res. 4: 783–789
Barnes PJ, Karin M . 1997 N. Engl. J. Med. 336: 1066–1071
Beg A, Baldwin Jr. A . 1993 Genes Dev. 7: 2064–2070
Beg A, Baltimore D . 1996 Science 274: 782–784
Bentires-Alj M, Hellin AC, Ameyar M, Chouaib S, Merville M, Bours V . 1999 Cancer Res. 59: 811–815
Bond M, Fabunmi RP, Baker AH, Newby AC . 1998 FEBS Lett. 1: 29–34
Borgstrom P, Bourdon M, Hillan KJ, Sriramarao P, Ferrara N . 1998 Prostate 1: 1–10
Brockman J, Scherer D, McKinsey T, Hall S, Qi X, Lee W, Ballard D . 1995 Mol. Cell. Biol. 15: 2809–2818
Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U . 1995 Science 267: 1485–1488
DiDonato J, Hayakawa M, Rothwarf D, Zandi E, Karin M . 1997 Nature 388: 548–554
Dong G, Chen Z, Koto T, Van Waes C . 1999 Cancer Res. 59: 3495–3504
Duffey D, Chen Z, Dong G, Ondrey F, Wolf J, Brown K, Siebenlist U, Waes C . 1999 Cancer Res. 59: 3468–3474
Duque JL, Loughlin KR, Adam RM, Kantoff PW, Zurakowski D, Freeman MR . 1999 Urology 3: 523–527
Ferrer FA, Miller LJ, Andrawis RI, Kurtzman SH, Albertsen PC, Laudone VP, Kreutzer DL . 1997 J. Urol. 6: 2329–2333
Ferrer FA, Miller LJ, Andrawis RI, Kurtzman SH, Albertsen PC, Laudone VP, Kreutzer DL . 1998 Urology 1: 161–167
Fidler IJ . 1990 Cancer Res. 50: 6130–6138
Fidler IJ, Ellis LM . 1994 Cell 79: 185–188
Folkman J . 1992 Semin. Cancer Biol. 3: 65–71
Garrido C, Saule S, Gospodarowicz D . 1993 Growth Factors 2: 109–117
Gilmore TD, Koedood M, Piffat KA, White DW . 1996 Oncogene 13: 1367–1378
Giri D, Ropiquet F, Ittmann M . 1999 Clin. Cancer Res. 5: 1063–1071
Greene GF, Kitadai Y, Pettaway CA, von Eschenbach AC, Bucana CD, Fidler IJ . 1997 Am. J. Pathol. 5: 1571–1582
Greenlee RT, Murray T, Bolden S, Wingo PA . 2000 CA Cancer J. Clin. 50: 7–33
Gum R, Wang H, Lengyel E, Juarez J, Boyd D . 1997 Oncogene 12: 1481–1493
Hamdy FC, Fadlon EJ, Cottam D, Lawry J, Thurrell W, Silcocks PB, Anderson JB, Williams JL, Rees RC . 1994 Br. J. Cancer 1: 177–182
Higgins KA, Perez JR, Coleman TA, Dorshkind K, McComas WA, Sarmiento UM, Rosen CA, Narayanan R . 1993 Proc. Natl. Acad. Sci. USA 90: 9901–9905
Hiraoka N, Allen E, Apel IJ, Gyetko MR, Weiss SJ . 1998 Cell 3: 365–377
Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M . 1998 EMBO J. 17: 4358–4369
Huang S, DeGuzman A, Bucana CD, Fidler IJ . 2000 Clin Cancer Res. 6: 2573–2581
Inoue K, Slaton JW, Eve BY, Kim SJ, Perrotte P, Balbay MD, Yano S, Bar-Eli M, Radinsky R, Pettaway CA, Dinney CP . 2000 Clin. Cancer Res. 5: 2104–2119
Jackson MW, Bentel JM, Tilley WD . 1997 J Urol. 6: 2323–2328
Kim J, Yu W, Kovalski K, Ossowski L . 1998 Cell 3: 353–362
Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM . 1992 Science 258: 1798–1801
Kuniyasu H, Troncoso P, Johnston D, Bucana CD, Tahara E, Fidler IJ, Pettaway CA . 2000 Clin. Cancer Res. 6: 2295–2308
Leung DW, Cachianes G, Kuang WH, Goeddel DV, Ferrara N . 1989 Science 246: 1306–1309
Levy AP, Levy NS, Wegner S, Goldberg MA . 1995 J. Biol. Chem. 22: 13333–13340
Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S . 1993 Proc. Natl. Acad. Sci. USA 21: 10193–10197
Melnyk O, Zimmerman M, Kim KJ, Shuman M . 1999 J. Urol. 3: 960–963
Meyskens FL, Buckmeier JA, McNulty SE, Tohidian NB . 1999 Clin. Cancer Res. 5: 1197–1202
Moore BB, Arenberg DA, Stoy K, Morgan T, Addison CL, Morris SB, Glass M, Wilke C, Xue YY, Sitterding S, Kunkel SL, Burdick MD, Strieter RM . 1999 Amer. J. Pathol. 5: 1503–1512
Mukaida N, Okamoto S, Ishikawa Y, Matsushima K . 1994 J. Leukoc. Biol. 56: 554–581
Nakamoto T, Chang CS, Li AK, Chodak GW . 1992 Cancer Res. 3: 571–577
Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ, Sledge GW . 1997 Mol. Cell. Biol. 17: 3629–3639
Pajonk F, Pajonk K, McBride WH . 1999 J. Natl. Cancer Inst. 22: 1956–1960
Palayoor ST, Youmell MY, Calderwood SK, Coleman CN, Price BD . 1999 Oncogene 51: 7389–7394
Puyraimond A, Weitzman JB, Babiole E, Menashi S . 1999 J. Cell. Sci. 9: 1283–1290
Ray JM, Stetler-Stevenson WG . 1994 Eur. Respir. J. 11: 2062–2072
Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS . 1998 Genes Dev. 7: 968–981
Ripple MO, Henry WF, Schwarze SR, Wilding G, Weindruch R . 1999 J. Natl. Cancer Inst. 14: 1227–1232
Sato H, Kita M, Seiki M . 1993 J. Biol. Chem. 31: 23460–23468
Sehgal G, Hua J, Bernhard EJ, Sehgal I, Thompson TC, Muschel RJ . 1998 Am. J. Pathol. 2: 591–596
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF . 1983 Science 219: 983–985
Stephenson RA, Dinney CP, Gohji K, Ordonez NG, Killion JJ, Fidler IJ . 1992 J. Natl. Cancer Inst. 12: 951–957
Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, Abraham JA . 1991 J. Biol. Chem. 266: 11947–11954
Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S, Baeuerle PA . 1995 EMBO J. 14: 2876–2883
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM . 1996 Science 274: 787–789
Veltri RW, Miller MC, Zhao G, Ng A, Marley GM, Wright Jr. GL, Vessella RL, Ralph D . 1999 Urology 1: 139–147
Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S . 1995 Genes Dev. 22: 2723–2735
Vilarete LH, Remick DG . 1996 Amer. J. Pathol. 149: 1685–1693
Wang CY, Mayo MW, Baldwin AS . 1996 Science 274: 784–787
Wang W, Abbruzzese JL, Evans DB, Chiao PJ . 1999 Oncogene 32: 4554–4563
Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ . 1999 Clin. Cancer Res. 5: 119–127
Yokoo T, Kitamura M . 1996 Amer. J. Physiol. 2: 123–130
Yoshida A, Yoshida S, Ishibashi T, Kuwano M, Inomata H . 1999 Invest Ophthalmol. Vis. Sci. 7: 1624–1629
Acknowledgements
We thank Dr P Chiao (Department of Surgical Oncology) for pLXSN–IκBαM, Dr B Su (Department of Immunology) for 2x NF-κB reporter constructs, Dr D Boyd (Department of Cancer Biology) for the pGL2–MMP-9 reporter, Dr K Xie (Department of Gastrointestinal Medical Oncology) for the pGL2–VEGF reporter, and Drs N Mukaida and K Matsushima (Kanazawa University, Kanazawa, Japan) for the pxp2-IL8-1481 promoter. This work was supported in part by Cancer Center Support Core grant CA16672 and grant R35-CA42107 (IJ Fidler) from the National Cancer Institute, National Institutes of Health. The authors are grateful to Walter Pagel for his critical editorial comments, and Vallery Bolden-Hill for expert assistance in the preparation of this manuscript.
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Huang, S., Pettaway, C., Uehara, H. et al. Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20, 4188–4197 (2001). https://doi.org/10.1038/sj.onc.1204535
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DOI: https://doi.org/10.1038/sj.onc.1204535
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