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Cancer Therapy: Preclinical

Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer

Jingjing Gong, Jianping Xie, Roble Bedolla, Paul Rivas, Divya Chakravarthy, James W. Freeman, Robert Reddick, Scott Kopetz, Amanda Peterson, Huamin Wang, Susan M. Fischer and Addanki P. Kumar
Jingjing Gong
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Jianping Xie
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Roble Bedolla
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Paul Rivas
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Divya Chakravarthy
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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James W. Freeman
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Robert Reddick
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Scott Kopetz
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Amanda Peterson
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Huamin Wang
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Susan M. Fischer
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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Addanki P. Kumar
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
Department of 1Urology, 2Medical Oncology, 3Pathology, 4Cancer Therapy and Research Center, 5South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and 7Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas
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DOI: 10.1158/1078-0432.CCR-13-1664
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Abstract

Purpose: Near equal rates of incidence and mortality emphasize the need for novel targeted approaches for better management of patients with pancreatic cancer. Inflammatory molecules NF-κB and STAT3 are overexpressed in pancreatic tumors. Inhibition of one protein allows cancer cells to survive using the other. The goal of this study is to determine whether targeting STAT3/NF-κB crosstalk with a natural product Nexrutine can inhibit inflammatory signaling in pancreatic cancer.

Experimental Design: HPNE, HPNE-Ras, BxPC3, Capan-2, MIA PaCa-2, and AsPC-1 cells were tested for growth, apoptosis, cyclooxygenase-2 (COX-2), NF-κB, and STAT3 level in response to Nexrutine treatment. Transient expression, gel shift, chromatin immunoprecipitation assay was used to examine transcriptional regulation of COX-2. STAT3 knockdown was used to decipher STAT3/NF-κB crosstalk. Histopathologic and immunoblotting evaluation was performed on BK5–COX-2 transgenic mice treated with Nexrutine. In vivo expression of prostaglandin receptor E-prostanoid 4 (EP4) was analyzed in a retrospective cohort of pancreatic tumors using a tissue microarray.

Results: Nexrutine treatment inhibited growth of pancreatic cancer cells through induction of apoptosis. Reduced levels and activity of STAT3, NF-κB, and their crosstalk led to transcriptional suppression of COX-2 and subsequent decreased levels of prostaglandin E2 (PGE2) and PGF2. STAT3 knockdown studies suggest STAT3 as negative regulator of NF-κB activation. Nexrutine intervention reduced the levels of NF-κB, STAT3, and fibrosis in vivo. Expression of prostaglandin receptor EP4 that is known to play a role in fibrosis was significantly elevated in human pancreatic tumors.

Conclusions: Dual inhibition of STAT3–NF-κB by Nexrutine may overcome problems associated with inhibition of either pathway. Clin Cancer Res; 1–15. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received June 18, 2013.
  • Revision received December 16, 2013.
  • Accepted December 27, 2013.
  • ©2014 American Association for Cancer Research.
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This OnlineFirst version was published on February 11, 2014
doi: 10.1158/1078-0432.CCR-13-1664

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Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer
Jingjing Gong, Jianping Xie, Roble Bedolla, Paul Rivas, Divya Chakravarthy, James W. Freeman, Robert Reddick, Scott Kopetz, Amanda Peterson, Huamin Wang, Susan M. Fischer and Addanki P. Kumar
Clin Cancer Res February 11 2014 DOI: 10.1158/1078-0432.CCR-13-1664

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Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer
Jingjing Gong, Jianping Xie, Roble Bedolla, Paul Rivas, Divya Chakravarthy, James W. Freeman, Robert Reddick, Scott Kopetz, Amanda Peterson, Huamin Wang, Susan M. Fischer and Addanki P. Kumar
Clin Cancer Res February 11 2014 DOI: 10.1158/1078-0432.CCR-13-1664
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