title: LLL12 inhibits endogenous and exogenous interleukin-6-induced STAT3 phosphorylation in human pancreatic cancer cells.
abstract: Pancreatic cancer is one of the most serious types of cancer, with a five-year survival rate at only 6%. There is a critical need to develop more effective treatments for pancreatic cancer. Growing evidence shows that chronic inflammation plays a crucial role in tumor initiation and progression. Here we demonstrated that the endogenous expression of the inflammatory cytokine interleukin-6 (IL-6) correlates with signal transducer and activator of transcription 3 (STAT3) phosphorylation in human pancreatic cancer cells. Inhibition of the endogenous IL-6/STAT3 pathway reduces cell viability. Exogenous IL-6 induces STAT3 phosphorylation, but differently induces phosphorylation of STAT3 upstream kinases, Janus kinase 1(JAK1), JAK2, and tyrosine kinase 2 (TYK2). Interestingly, LLL12, a nonpeptide, cell-permeable small molecule, selectively blocked exogenous IL-6-induced STAT3 phosphorylation and nuclear translocation in both PANC-1 and ASPC-1 pancreatic cancer cell lines independently of the phosphorylation of JAK1, JAK2, and TYK2. These results suggest that the inhibition of endogenous and exogenous IL-6-mediated STAT3 signaling may be a potential therapeutic approach for pancreatic cancer.
authors: Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA.
authors: Aiguo
authors: A
authors: Liu
authors: Yan
authors: Y
authors: Liu
authors: Pui-Kai
authors: PK
authors: Li
authors: Chenglong
authors: C
authors: Li
authors: Jiayuh
authors: J
authors: Lin
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000880:Anthraquinones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D053634:TYK2 Kinase / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000880:Anthraquinones; D015850:Interleukin-6; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D053634:TYK2 Kinase; D000093242:Interleukin-6 Inhibitors; C549232:LLL12 compound; C494086:STAT3 protein, human; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C070139:TYK2 protein, human