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, Addanki P Kumar

Research output: Contribution to journalArticle

46 Citations (Scopus)

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-kB 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-kB 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-kB, 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-kB, 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-kB by Nexrutine may overcome problems associated with inhibition of either pathway.

Original languageEnglish (US)
Pages (from-to)1259-1273
Number of pages15
JournalClinical Cancer Research
Volume20
Issue number5
DOIs
StatePublished - 2014

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Cyclooxygenase 2
Pancreatic Neoplasms
NF-kappa B
Prostaglandins
Receptors, Prostaglandin E, EP4 Subtype
Neoplasms
Fibrosis
Apoptosis
Dinoprost
Chromatin Immunoprecipitation
Growth
Biological Products
Dinoprostone
Immunoblotting
Transgenic Mice
Nexrutine
Research Design
Gels
Mortality
Incidence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Combined targeting of STAT3/NF-κB/COX-2/EP4 for effective management of pancreatic cancer. / Gong, Jingjing; Xie, Jianping; Bedolla, Roble; Rivas, Paul; Chakravarthy, Divya; Freeman, James W; Reddick, Robert; Kopetz, Scott; Peterson, Amanda; Wang, Huamin; Fischer, Susan M.; Kumar, Addanki P.

In: Clinical Cancer Research, Vol. 20, No. 5, 2014, p. 1259-1273.

Research output: Contribution to journalArticle

Gong, J, Xie, J, Bedolla, R, Rivas, P, Chakravarthy, D, Freeman, JW, Reddick, R, Kopetz, S, Peterson, A, Wang, H, Fischer, SM & Kumar, AP 2014, 'Combined targeting of STAT3/NF-κB/COX-2/EP4 for effective management of pancreatic cancer', Clinical Cancer Research, vol. 20, no. 5, pp. 1259-1273. https://doi.org/10.1158/1078-0432.CCR-13-1664
Gong, Jingjing ; Xie, Jianping ; Bedolla, Roble ; Rivas, Paul ; Chakravarthy, Divya ; Freeman, James W ; Reddick, Robert ; Kopetz, Scott ; Peterson, Amanda ; Wang, Huamin ; Fischer, Susan M. ; Kumar, Addanki P. / Combined targeting of STAT3/NF-κB/COX-2/EP4 for effective management of pancreatic cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 5. pp. 1259-1273.
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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-kB 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-kB 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-kB, 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-kB, 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-kB by Nexrutine may overcome problems associated with inhibition of either pathway.",
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AU - Gong, Jingjing

AU - Xie, Jianping

AU - Bedolla, Roble

AU - Rivas, Paul

AU - Chakravarthy, Divya

AU - Freeman, James W

AU - Reddick, Robert

AU - Kopetz, Scott

AU - Peterson, Amanda

AU - Wang, Huamin

AU - Fischer, Susan M.

AU - Kumar, Addanki P

PY - 2014

Y1 - 2014

N2 - 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-kB 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-kB 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-kB, 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-kB, 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-kB by Nexrutine may overcome problems associated with inhibition of either pathway.

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