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

55 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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