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 journalArticlepeer-review

49 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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