title: Combined targeting of STAT3/NF-κB/COX-2/EP4 for effective management of pancreatic cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Authors' Affiliations: Department of Urology, Medical Oncology, Pathology, Cancer Therapy and Research Center, South Texas Veterans Health Care System, The University of Texas Health Science Center, San Antonio; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston; and Department of carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors: Jingjing
authors: J
authors: Gong
authors: Jianping
authors: J
authors: Xie
authors: Roble
authors: R
authors: Bedolla
authors: Paul
authors: P
authors: Rivas
authors: Divya
authors: D
authors: Chakravarthy
authors: James W
authors: JW
authors: Freeman
authors: Robert
authors: R
authors: Reddick
authors: Scott
authors: S
authors: Kopetz
authors: Amanda
authors: A
authors: Peterson
authors: Huamin
authors: H
authors: Wang
authors: Susan M
authors: SM
authors: Fischer
authors: Addanki P
authors: AP
authors: Kumar
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; C512605:Nexrutine; D010936:Plant Extracts; D058309:Receptors, Prostaglandin E, EP4 Subtype; D050796:STAT3 Transcription Factor; D051546:Cyclooxygenase 2