Abstract
The development of more effective prevention and treatment strategies for solid tumors is limited by an incomplete understanding of the critical growth pathways that are activated in carcinogenesis. Signal transducers and activators of transcription (STAT) proteins have been linked to transformation and tumor progression. Several approaches have been used to block STAT3 in cancer cells resulting in reduced proliferation and apoptosis. We tested the hypothesis that blocking STAT3 activation using a transcription factor decoy approach would decrease tumor growth and STAT3 target gene expression in vivo. In a xenograft model of squamous cell carcinoma of the head and neck (SCCHN), daily administration of the STAT3 decoy (25 μg) resulted in decreased tumor volumes, abrogation of STAT3 activation, and decreased expression of STAT3 target genes (VEGF, Bcl-xL, and cyclin D1) compared to treatment with a mutant control decoy. Blockade of STAT3 with the STAT3 decoy also induced apoptosis and decreased proliferation, an effect that was augmented when the STAT3 decoy was combined with cisplatin, both in vitro and in vivo. These results suggest that a transcription factor decoy approach may be used to target STAT3 in cancers that demonstrate increased STAT3 activation including SCCHN.
Similar content being viewed by others
References
Akira S . (2000). Oncogene, 19, 2607–2611.
Bielinska A, Shivdasani RA, Zhang LQ and Nabel GJ . (1990). Science, 250, 997–1000.
Bishop-Bailey D and Hla T . (1999). J. Biol. Chem., 274, 17042–17048.
Boccaccio C, Ando M, Tamagnone L, Bardelli A, Michieli P, Battistini C and Comoglio PM . (1998). Nature, 391, 285–288.
Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA and Jove R . (2001). Proc. Natl. Acad. Sci. USA, 98, 7319–7324.
Bowman T, Garcia R, Turkson J and Jove R . (2000). Oncogene, 19, 2474–2488.
Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C and Darnell Jr JE . (1999). Cell, 98, 295–303.
Catlett-Falcone R, Dalton WS and Jove R . (1999a). Curr. Opin. Oncol., 11, 490–496.
Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS and Jove R . (1999b). Immunity, 10, 105–115.
Darnell Jr JE . (1997). Science, 277, 1630–1635.
Folkman J . (1997). Exs, 79, 1–8.
Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR, Connors RW and Bridges AJ . (1994). Science, 265, 1093–1095.
Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, Cox CE, Falcone R, Fairclough R, Parsons S, Laudano A, Gazit A, Levitzki A, Kraker A and Jove R . (2001). Oncogene, 20, 2499–2513.
Gouilleux-Gruart V, Gouilleux F, Desaint C, Claisse JF, Capiod JC, Delobel J, Weber-Nordt R, Dusanter-Fourt I, Dreyfus F, Groner B and Prin L . (1996). Blood, 87, 1692–1697.
Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y and Kim JD . (2000a). Proc. Natl. Acad. Sci. USA, 97, 4227–4232.
Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD and Tweardy DJ . (1998). J. Natl. Cancer Inst., 90, 824–832.
Grandis JR, Zeng Q and Drenning SD . (2000b). Laryngoscope, 110, 868–874.
Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D and Johnson RS . (1999). Cancer Res., 59, 1592–1598.
Hanahan D and Folkman J . (1996). Cell, 86, 353–364.
Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.
Huang M, Page C, Reynolds RK and Lin J . (2000). Gynecol Oncol, 79, 67–73.
Kawamura I, Morishita R, Tomita N, Lacey E, Aketa M, Tsujimoto S, Manda T, Tomoi M, Kida I, Higaki J, Kaneda Y, Shimomura K and Ogihara T . (1999). Gene Therapy, 6, 91–97.
Kraker AJ, Hartl BG, Amar AM, Barvian MR, Showalter HD and Moore CW . (2000). Biochem. Pharmacol., 60, 885–898.
Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi S, Mai JC, Robbins PD, Gadiparthi S, Burke NA, Watkins SF and Grandis JR . (2003). Proc. Natl. Acad. Sci. USA, 100, 4138–4143.
Levy DE and Darnell Jr JE . (2002). Nat. Rev. Mol. Cell. Biol., 3, 651–662.
Li L and Shaw PE . (2002). J. Biol. Chem., 277, 17397–17405.
Lim R, Zaheer A, Yorek MA, Darby CJ and Oberley LW . (2000). J. Neurochem., 74, 596–602.
Mann MJ and Dzau VJ . (2000). J. Clin. Invest., 106, 1071–1075.
Mayer F, Honecker F, Looijenga LH and Bokemeyer C . (2003). Ann. Oncol., 14, 825–832.
Millauer B, Shawver LK, Plate KH, Risau W and Ullrich A . (1994). Nature, 367, 576–579.
Nabel EG, Plautz G and Nabel GJ . (1990). Science, 249, 1285–1288.
Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, Kitaoka T, Fukada T, Hibi M and Hirano T . (1996). EMBO J., 15, 3651–3658.
Nielsen M, Kaestel CG, Eriksen KW, Woetmann A, Stokkedal T, Kaltoft K, Geisler C, Ropke C and Odum N . (1999). Leukemia, 13, 735–738.
Niu G, Heller R, Catlett-Falcone R, Coppola D, Jaroszeski M, Dalton W, Jove R and Yu H . (1999). Cancer Res., 59, 5059–5063.
Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R and Yu H . (2002). Oncogene, 21, 2000–2008.
Park SH, Liu X, Hennighausen L, Davey HW and Waxman DJ . (1999). J. Biol. Chem., 274, 7421–7430.
Plate KH, Breier G, Weich HA and Risau W . (1992). Nature, 359, 845–848.
Rak J, Mitsuhashi Y, Sheehan C, Tamir A, Viloria-Petit A, Filmus J, Mansour SJ, Ahn NG and Kerbel RS . (2000). Cancer Res., 60, 490–498.
Takeda T, Kurachi H, Yamamoto T, Homma H, Morishige K, Miyake A and Murata Y . (1997). J. Endocrinol., 153, R1–3.
Takeuchi S, Imafuku I, Waragai M, Roth C, Kanazawa I, Buettner R, Mouradian MM and Okazawa H . (1999). Brain Res. Mol. Brain Res., 74, 208–216.
Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M, Frank DA, Holzman LB, Wu J, Sebti S and Jove R . (1999). Mol. Cell. Biol., 19, 7519–7528.
Turkson J, Ryan D, Kim JS, Zhang Y, Chen Z, Haura E, Laudano A, Sebti S, Hamilton AD and Jove R . (2001). J. Biol. Chem., 276, 45443–45455.
Veikkola T and Alitalo K . (1999). Semin. Cancer Biol., 9, 211–220.
Veikkola T, Karkkainen M, Claesson-Welsh L and Alitalo K . (2000). Cancer Res., 60, 203–212.
von Knethen A, Lotero A and Brune B . (1998). Oncogene, 17, 387–394.
Wagner BJ, Hayes TE, Hoban CJ and Cochran BH . (1990). EMBO J., 9, 4477–4484.
Wang LH, Yang XY, Kirken RA, Resau JH and Farrar WL . (2000). Blood, 95, 1249–1257.
Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL and Xie K . (2003). Oncogene, 22, 319–329.
Wong P, Severns CW, Guyer NB and Wright TM . (1994). Mol. Cell. Biol., 14, 914–922.
Xi S, Zhang Q, Dyer KF, Lerner EC, Smithgall TE, Gooding WE, Kamens J and Grandis JR . (2003). J. Biol. Chem., 278, 31574–31583.
Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J and Jove R . (1995). Science, 269, 81–83.
Acknowledgements
This work was supported in part by funding from NIH (NCI) Grants 1 P50 CA097190-01A1 and R01CA 101840-01.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Xi, S., Gooding, W. & Grandis, J. In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy. Oncogene 24, 970–979 (2005). https://doi.org/10.1038/sj.onc.1208316
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208316
- Springer Nature Limited
Keywords
This article is cited by
-
Targeting the IL-6/JAK/STAT3 signalling axis in cancer
Nature Reviews Clinical Oncology (2018)
-
SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer
Oncogene (2016)
-
Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening
Cell Death & Disease (2014)
-
A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-κB
BMC Cell Biology (2011)