Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 100 (7): 4138-4143

Copyright © 2003 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth

Paul L. Leong*,{dagger}, Genevieve A. Andrews*,{dagger}, Daniel E. Johnson{ddagger},§, Kevin F. Dyer*, Sichuan Xi*, Jeffrey C. Mai, Paul D. Robbins, Seshu Gadiparthi*, Nancy A. Burke||, Simon F. Watkins||, and Jennifer Rubin Grandis*,§,**

Departments of *Otolaryngology, {ddagger}Medicine, §Pharmacology, Molecular Genetics and Biochemistry, and ||Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15260

Received for publication August 7, 2002.

Abstract: The transcription factor signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a variety of cancers including squamous cell carcinoma of the head and neck (SCCHN). Previous investigations have demonstrated that activated Stat3 contributes to a loss of growth control and transformation. To investigate the therapeutic potential of blocking Stat3 in cancer cells, we developed a transcription factor decoy to selectively abrogate activated Stat3. The Stat3 decoy was composed of a 15-mer double-stranded oligonucleotide, which corresponded closely to the Stat3 response element within the c-fos promoter. The Stat3 decoy bound specifically to activated Stat3 and blocked binding of Stat3 to a radiolabeled Stat3 binding element. By contrast, a mutated version of the decoy that differed by only a single base pair did not bind the activated Stat3 protein. Treatment of head and neck cancer cells with the Stat3 decoy inhibited proliferation and Stat3-mediated gene expression, but did not decrease the proliferation of normal oral keratinocytes. Thus, disruption of activated Stat3 by using a transcription factor decoy approach may serve as a novel therapeutic strategy for cancers characterized by constitutive Stat3 activation.


{dagger} P.L.L. and G.A.A. contributed equally to this work.

** To whom correspondence should be addressed. E-mail: jgrandis{at}pitt.edu.

Edited by James E. Darnell, Jr., The Rockefeller University, New York, NY, and approved December 2, 2002

This paper was submitted directly (Track II) to the PNAS office.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Targeting Blockage of STAT3 in Hepatocellular Carcinoma Cells Augments NK Cell Functions via Reverse Hepatocellular Carcinoma-Induced Immune Suppression.
X. Sun, Q. Sui, C. Zhang, Z. Tian, and J. Zhang (2013)
Mol. Cancer Ther. 12, 2885-2896
   Abstract »    Full Text »    PDF »
Targeting Stat3 Abrogates EGFR Inhibitor Resistance in Cancer.
M. Sen, S. Joyce, M. Panahandeh, C. Li, S. M. Thomas, J. Maxwell, L. Wang, W. E. Gooding, D. E. Johnson, and J. R. Grandis (2012)
Clin. Cancer Res. 18, 4986-4996
   Abstract »    Full Text »    PDF »
First-in-Human Trial of a STAT3 Decoy Oligonucleotide in Head and Neck Tumors: Implications for Cancer Therapy.
M. Sen, S. M. Thomas, S. Kim, J. I. Yeh, R. L. Ferris, J. T. Johnson, U. Duvvuri, J. Lee, N. Sahu, S. Joyce, et al. (2012)
Cancer Discovery 2, 694-705
   Abstract »    Full Text »    PDF »
Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies.
P. Sansone and J. Bromberg (2012)
J. Clin. Oncol. 30, 1005-1014
   Abstract »    Full Text »    PDF »
Cross-talk between Phospho-STAT3 and PLC{gamma}1 Plays a Critical Role in Colorectal Tumorigenesis.
P. Zhang, Y. Zhao, X. Zhu, D. Sedwick, X. Zhang, and Z. Wang (2011)
Mol. Cancer Res. 9, 1418-1428
   Abstract »    Full Text »    PDF »
Overexpression of GRIM-19 in Cancer Cells Suppresses STAT3-Mediated Signal Transduction and Cancer Growth.
T. Okamoto, T. Inozume, H. Mitsui, M. Kanzaki, K. Harada, N. Shibagaki, and S. Shimada (2010)
Mol. Cancer Ther. 9, 2333-2343
   Abstract »    Full Text »    PDF »
Long-term Nicotine Exposure-Induced Chemoresistance Is Mediated by Activation of Stat3 and Downregulation of ERK1/2 via nAChR and Beta-Adrenoceptors in Human Bladder Cancer Cells.
R. J. Chen, Y. S. Ho, H. R. Guo, and Y. J. Wang (2010)
Toxicol. Sci. 115, 118-130
   Abstract »    Full Text »    PDF »
New Strategies in Head and Neck Cancer: Understanding Resistance to Epidermal Growth Factor Receptor Inhibitors.
L. F. Chen, E. E. W. Cohen, and J. R. Grandis (2010)
Clin. Cancer Res. 16, 2489-2495
   Abstract »    Full Text »    PDF »
CADPE Suppresses Cyclin D1 Expression in Hepatocellular Carcinoma by Blocking IL-6-induced STAT3 Activation.
C. WON, C. S. LEE, J.-K. LEE, T.-J. KIM, K.-H. LEE, Y. M. YANG, Y.-N. KIM, S.-K. YE, and M.-H. CHUNG (2010)
Anticancer Res 30, 481-488
   Abstract »    Full Text »    PDF »
Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene.
V. Williams, S. Brichler, N. Radjef, P. Lebon, A. Goffard, D. Hober, R. Fagard, D. Kremsdorf, P. Deny, and E. Gordien (2009)
J. Gen. Virol. 90, 2759-2767
   Abstract »    Full Text »    PDF »
IL-6 Regulates MMP-10 Expression via JAK2/STAT3 Signaling Pathway in a Human Lung Adenocarcinoma Cell Line.
X. ZHANG, P. YIN, D. DI, G. LUO, L. ZHENG, J. WEI, J. ZHANG, Y. SHI, J. ZHANG, and N. XU (2009)
Anticancer Res 29, 4497-4501
   Abstract »    Full Text »    PDF »
Polymer beacons for luminescence and magnetic resonance imaging of DNA delivery.
J. M. Bryson, K. M. Fichter, W.-J. Chu, J.-H. Lee, J. Li, L. A. Madsen, P. M. McLendon, and T. M. Reineke (2009)
PNAS 106, 16913-16918
   Abstract »    Full Text »    PDF »
17-Hydroxy-jolkinolide B Inhibits Signal Transducers and Activators of Transcription 3 Signaling by Covalently Cross-Linking Janus Kinases and Induces Apoptosis of Human Cancer Cells.
Y. Wang, X. Ma, S. Yan, S. Shen, H. Zhu, Y. Gu, H. Wang, G. Qin, and Q. Yu (2009)
Cancer Res. 69, 7302-7310
   Abstract »    Full Text »    PDF »
Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death.
C. Li, Y. Zang, M. Sen, R. J. Leeman-Neill, D. SK. Man, J. R. Grandis, and D. E. Johnson (2009)
Mol. Cancer Ther. 8, 2211-2220
   Abstract »    Full Text »    PDF »
Inhibitory Effects of Decoy-ODN Targeting Activated STAT3 on Human Glioma Growth In Vivo.
J. SHEN, R. LI, and G. LI (2009)
In Vivo 23, 237-243
   Abstract »    Full Text »    PDF »
The Incidence, Correlation with Tumor-Infiltrating Inflammation, and Prognosis of Phosphorylated STAT3 Expression in Human Gliomas.
M. Abou-Ghazal, D. S. Yang, W. Qiao, C. Reina-Ortiz, J. Wei, L.-Y. Kong, G. N. Fuller, N. Hiraoka, W. Priebe, R. Sawaya, et al. (2008)
Clin. Cancer Res. 14, 8228-8235
   Abstract »    Full Text »    PDF »
The PIM1 Kinase Is a Critical Component of a Survival Pathway Activated by Docetaxel and Promotes Survival of Docetaxel-treated Prostate Cancer Cells.
M. Zemskova, E. Sahakian, S. Bashkirova, and M. Lilly (2008)
J. Biol. Chem. 283, 20635-20644
   Abstract »    Full Text »    PDF »
Genomic dissection of the cytokine-controlled STAT5 signaling network in liver.
A. Hosui and L. Hennighausen (2008)
Physiol Genomics 34, 135-143
   Abstract »    Full Text »    PDF »
Combined Targeting of Epidermal Growth Factor Receptor, Signal Transducer and Activator of Transcription-3, and Bcl-XL Enhances Antitumor Effects in Squamous Cell Carcinoma of the Head and Neck.
A. L. Boehm, M. Sen, R. Seethala, W. E. Gooding, M. Freilino, S. M. Y. Wong, S. Wang, D. E. Johnson, and J. R. Grandis (2008)
Mol. Pharmacol. 73, 1632-1642
   Abstract »    Full Text »    PDF »
Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas.
E. C. Brantley and E. N. Benveniste (2008)
Mol. Cancer Res. 6, 675-684
   Abstract »    Full Text »    PDF »
Immunohistochemical Analysis of Phosphotyrosine Signal Transducer and Activator of Transcription 3 and Epidermal Growth Factor Receptor Autocrine Signaling Pathways in Head and Neck Cancers and Metastatic Lymph Nodes.
R. R. Seethala, W. E. Gooding, P. N. Handler, B. Collins, Q. Zhang, J. M. Siegfried, and J. R. Grandis (2008)
Clin. Cancer Res. 14, 1303-1309
   Abstract »    Full Text »    PDF »
Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway.
N. de la Iglesia, G. Konopka, S. V. Puram, J. A. Chan, R. M. Bachoo, M. J. You, D. E. Levy, R. A. DePinho, and A. Bonni (2008)
Genes & Dev. 22, 449-462
   Abstract »    Full Text »    PDF »
Manipulating and understanding antibiotic production in Streptomyces coelicolor A3(2) with decoy oligonucleotides.
M. McArthur and M. J. Bibb (2008)
PNAS 105, 1020-1025
   Abstract »    Full Text »    PDF »
Leptin-mediated Cell Survival Signaling in Hippocampal Neurons Mediated by JAK STAT3 and Mitochondrial Stabilization.
Z. Guo, H. Jiang, X. Xu, W. Duan, and M. P. Mattson (2008)
J. Biol. Chem. 283, 1754-1763
   Abstract »    Full Text »    PDF »
Effects of Plasmid-Based Stat3-Specific Short Hairpin RNA and GRIM-19 on PC-3M Tumor Cell Growth.
L. Zhang, L. Gao, Y. Li, G. Lin, Y. Shao, K. Ji, H. Yu, J. Hu, D. V. Kalvakolanu, D. J. Kopecko, et al. (2008)
Clin. Cancer Res. 14, 559-568
   Abstract »    Full Text »    PDF »
Bcl-2 Orchestrates a Cross-talk between Endothelial and Tumor Cells that Promotes Tumor Growth.
T. Kaneko, Z. Zhang, M. G. Mantellini, E. Karl, B. Zeitlin, M. Verhaegen, M. S. Soengas, M. Lingen, R. M. Strieter, G. Nunez, et al. (2007)
Cancer Res. 67, 9685-9693
   Abstract »    Full Text »    PDF »
Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance.
J. Zhou, J. Wulfkuhle, H. Zhang, P. Gu, Y. Yang, J. Deng, J. B. Margolick, L. A. Liotta, E. Petricoin III, and Y. Zhang (2007)
PNAS 104, 16158-16163
   Abstract »    Full Text »    PDF »
Response: Re: Decreased STAT1 Expression by Promoter Methylation in Squamous Cell Carcinogenesis.
J. R. Grandis, J. Califano, I. Smith, and S. Mithani (2007)
J Natl Cancer Inst 99, 1344
   Full Text »    PDF »
Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells.
C. Agarwal, A. Tyagi, M. Kaur, and R. Agarwal (2007)
Carcinogenesis 28, 1463-1470
   Abstract »    Full Text »    PDF »
Antiproliferative Mechanisms of a Transcription Factor Decoy Targeting Signal Transducer and Activator of Transcription (STAT) 3: The Role of STAT1.
V. W. Y. Lui, A. L. Boehm, P. Koppikar, R. J. Leeman, D. Johnson, M. Ogagan, E. Childs, M. Freilino, and J. R. Grandis (2007)
Mol. Pharmacol. 71, 1435-1443
   Abstract »    Full Text »    PDF »
Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical Implications.
S. Huang (2007)
Clin. Cancer Res. 13, 1362-1366
   Abstract »    Full Text »    PDF »
Construction of a novel DNA decoy that inhibits the oncogenic {beta}-catenin/T-cell factor pathway..
Y. Seki, H. Yamamoto, C. Yee Ngan, M. Yasui, N. Tomita, K. Kitani, I. Takemasa, M. Ikeda, M. Sekimoto, N. Matsuura, et al. (2006)
Mol. Cancer Ther. 5, 985-994
   Abstract »    Full Text »    PDF »
Decreased STAT1 Expression by Promoter Methylation in Squamous Cell Carcinogenesis.
S. Xi, K. F. Dyer, M. Kimak, Q. Zhang, W. E. Gooding, J. R. Chaillet, R. L. Chai, R. E. Ferrell, B. Zamboni, J. Hunt, et al. (2006)
J Natl Cancer Inst 98, 181-189
   Abstract »    Full Text »    PDF »
Epigenetic modification of SOCS-1 differentially regulates STAT3 activation in response to interleukin-6 receptor and epidermal growth factor receptor signaling through JAK and/or MEK in head and neck squamous cell carcinomas.
T. L. Lee, J. Yeh, C. Van Waes, and Z. Chen (2006)
Mol. Cancer Ther. 5, 8-19
   Abstract »    Full Text »    PDF »
Down-Regulation of Signal Transducer and Activator of Transcription 3 Expression Using Vector-Based Small Interfering RNAs Suppresses Growth of Human Prostate Tumor In vivo.
L. Gao, L. Zhang, J. Hu, F. Li, Y. Shao, D. Zhao, D. V. Kalvakolanu, D. J. Kopecko, X. Zhao, and D.-Q. Xu (2005)
Clin. Cancer Res. 11, 6333-6341
   Abstract »    Full Text »    PDF »
Signal Transducer and Activator of Transcription 3 Is a Key Regulator of Keratinocyte Survival and Proliferation following UV Irradiation.
S. Sano, K. S. Chan, M. Kira, K. Kataoka, S. Takagi, M. Tarutani, S. Itami, K. Kiguchi, M. Yokoi, K. Sugasawa, et al. (2005)
Cancer Res. 65, 5720-5729
   Abstract »    Full Text »    PDF »
Novel single-stranded oligonucleotides that inhibit signal transducer and activator of transcription 3 induce apoptosis in vitro and in vivo in prostate cancer cell lines.
B. E. Barton, T. F. Murphy, P. Shu, H. F. Huang, M. Meyenhofen, and A. Barton (2004)
Mol. Cancer Ther. 3, 1183-1191
   Abstract »    Full Text »    PDF »
SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION: INSIGHTS INTO THE MOLECULAR BASIS OF ORAL CANCER.
H. Siavash, N.G. Nikitakis, and J.J. Sauk (2004)
Critical Reviews in Oral Biology & Medicine 15, 298-307
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor Receptor-Mediated Activation of Stat3 during Multistage Skin Carcinogenesis.
K. S. Chan, S. Carbajal, K. Kiguchi, J. Clifford, S. Sano, and J. DiGiovanni (2004)
Cancer Res. 64, 2382-2389
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882