Objectives We investigated the signaling pathways activated in response to Interleukin (IL-6) in pancreatic cell lines, with a focus on signal transducer and activator of transcription 3 (STAT3) and proto-oncogene serine/threonine-protein (Pim-1) kinase. Pancreatic cancer remains one of the most devastating and elusive malignancies among neoplastic disease. In 2010, over 43,000 new cases of pancreatic cancer and 36,000 pancreatic cancer associated deaths were predicted1. Due to its typically Rabbit polyclonal to EVI5L late presentation and refractory nature toward treatment, pancreatic cancer remains the fourth leading cause of cancer-related death in the United States. While pancreatic cancer involves deregulation across multiple cellular pathways, one common theme is the activation of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). More 52232-67-4 manufacture than 90% of pancreatic tumors carry an activating KRAS mutation, and this is believed to be an initiating event in oncogenesis2. Over-activation of KRAS stimulates fibroblasts in the stroma and recruits inflammatory mediators to the tumor microenvironment, both of which exacerbate tumor growth and invasion by up-regulating interleukin-6 (IL-6) production3;4. IL-6 is a pleiotropic cytokine produced by a variety of cell types including macrophages, fibroblasts, endothelial cells, and myeloid cells. In the context of pancreatic cancer, it upregulates the expression of cytokines that enable proliferation, immune evasion, and resistance to apoptosis5. IL-6 binds to a composite receptor composed of a specific 80 kDa alpha subunit (IL-6R, gp80) and two subunits of gp130 receptor which transduce a signal upon ligand binding6. Upon binding IL-6, gp130 activates the Janus kinase (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway by inducing cross-phosphorylation of the Jak2 proteins associated with the cytoplasmic side of the receptor7. Jak2 then phosphorylates key tyrosine residues on the gp130 receptor. These phospho-tyrosine residues then serve as a docking site for the recruitment of STAT3 proteins, which act as cellular mediators of IL-6. STAT3 is an oncogene that is activated by tyrosine phosphorylation (P-STAT3) in response to extracellular signals and JAK pathway activation. Once phosphorylated through binding to activated JAK proteins, P-STAT3 forms dimers and translocates to the nucleus where it regulates the transcription of a key set of target genes involved in 52232-67-4 manufacture proliferation, survival, cell cycle progression, angiogenesis, and immunosuppression8. Several lines of evidence suggest that IL-6 stimulates cancer growth by activation of STAT38. STAT3 is constitutively expressed in a multitude of human cancers, including pancreatic, and has a well-established role in neoplastic development9. Elevated levels of P-STAT3 correlate with increased IL-6 production in pancreatic cancer cell lines10. Moreover, activated STAT3 can also upregulate IL-6 expression11, giving rise to a positive feedback loop 52232-67-4 manufacture that impinges on 52232-67-4 manufacture tumor progression, invasion, and chemo-resistance12. The proto-oncogene Pim-1 is emerging as a target of STAT3-driven transcription that plays a key role in tumor progression and transformation. Pim-1 is a constitutively active serine/threonine kinase which has overlapping homology and function with Pim-2 and Pim-3 kinases13. Pim-1 kinase was identified as a gene induced by KRAS oncogenic activation in pancreatic carcinogenesis14, and is over-expressed in a wide range of cancers, including pancreatic tumors. Unlike other serine/threonine kinases, Pim-1 is regulated at the transcriptional and translational levels, with phosphorylation serving to stabilize the protein but not being required for activity (for a comprehensive review of Pim-1 kinase please see15). Pim-1 is associated with cell cycle progression, survival, and legislation of transcription factors16;17. Because many focuses on of Pim-1 phosphorylation rest within the cell cycle, Pim-1 activity is definitely closely linked to the G1/H and G2/M checkpoints and cellular expansion status13;18;19. While Pim-1 only is definitely only weakly oncogenic, it synergistically interacts with c-Myc to travel change by stabilizing the c-myc protein and enabling service of c-Myc transcriptional focuses on20;21. Pim-1 is definitely also strongly connected with evasion of apoptosis and drug resistance22;23. This offers been observed extensively in prostate malignancy, where IL-6 mediated.