TY - JOUR
T1 - Combined targeting of STAT3/NF-κB/COX-2/EP4 for effective management of pancreatic cancer
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.
AB - 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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U2 - 10.1158/1078-0432.CCR-13-1664
DO - 10.1158/1078-0432.CCR-13-1664
M3 - Article
C2 - 24520096
AN - SCOPUS:84895815843
SN - 1078-0432
VL - 20
SP - 1259
EP - 1273
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -