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

ABSTRACT: 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-?B 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-?B crosstalk with a natural product Nexrutine can inhibit inflammatory signaling in pancreatic cancer.HPNE, HPNE-Ras, BxPC3, Capan-2, MIA PaCa-2, and AsPC-1 cells were tested for growth, apoptosis, cyclooxygenase-2 (COX-2), NF-?B, 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-?B 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.Nexrutine treatment inhibited growth of pancreatic cancer cells through induction of apoptosis. Reduced levels and activity of STAT3, NF-?B, 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-?B activation. Nexrutine intervention reduced the levels of NF-?B, 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.Dual inhibition of STAT3-NF-?B by Nexrutine may overcome problems associated with inhibition of either pathway.

SUBMITTER: Gong J

PROVIDER: S-EPMC3969421 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other

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

Gong Jingjing J Xie Jianping J Bedolla Roble R Rivas Paul P Chakravarthy Divya D Freeman James W JW Reddick Robert R Kopetz Scott S Peterson Amanda A Wang Huamin H Fischer Susan M SM Kumar Addanki P AP

Clinical cancer research : an official journal of the American Association for Cancer Research 20140211 5

<h4>Purpose</h4>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.<h4>Experime ...[more]

PMID: 24520096

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Project description:BackgroundEpithelioid sarcoma (EpS) is a high-grade malignant soft-tissue sarcoma characterized by local recurrences and distant metastases. Effective treatments for EpS have not been established and thus novel therapeutic approaches against EpS are urgently required. mTOR inhibitors exert antitumor effects on several malignancies but AKT reactivation by mTOR inhibition attenuates the antitumor effects of mTOR inhibitors. This reactivation is receptor tyrosine kinase (RTK)-dependent due to a release of negative feedback inhibition. We found that c-MET was the most highly activated RTK in two human EpS cell lines, Asra-EPS and VAESBJ. Here we investigated the functional and therapeutic relevance of mTOR and/or c-MET signaling pathways in EpS both in vitro and in vivo.MethodsWe first examined the effects of an mTOR inhibitor, RAD001 (everolimus), on cell proliferation, cell cycle, AKT/mTOR signaling, and xenograft tumor growth in EpS cell lines. Next, we determined whether RAD001-induced AKT reactivation was blocked by silencing of c-MET or treatment with a selective c-MET inhibitor, INC280. Finally, we evaluated the antitumor effects of RAD001 combined with INC280 on EpS cell lines compared with either single agent or control in vitro and in vivo.ResultsConstitutive AKT phosphorylation was observed in Asra-EPS and VAESBJ cells. RAD001 suppressed EpS cell growth by inducing cell cycle arrest but enhanced AKT phosphorylation, which resulted in intrinsic resistance to mTOR inhibitors. In both EpS cell lines, RAD001-induced AKT phosphorylation was dependent on c-MET signaling. INC280 inhibited phosphorylation of c-MET and its downstream molecules, and decreased RAD001-induced phosphorylation of both AKT and ERK in EpS. Compared with a single agent or control, the combination of RAD001 and INC280 exerted superior antitumor effects on the growth of EpS cell lines in vitro and in vivo.ConclusionsTargeting of mTOR and c-MET signaling pathways significantly abrogates the growth of EpS in preclinical models and may be a promising therapeutic approach for patients with EpS.

Dataset Information

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

Publications

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

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