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Article Publish Status: FREE
Abstract Title:

Combined targeting of STAT3/NF-κB/COX-2/EP4 for effective management of pancreatic cancer.

Abstract Source:

Clin Cancer Res. 2014 Mar 1 ;20(5):1259-73. Epub 2014 Feb 11. PMID: 24520096

Abstract Author(s):

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

Article Affiliation:

Jingjing Gong

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.

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