Nicotinamide phosphoribosyltransferase and prostaglandin H2 synthase 2 are up-regulated in human pancreatic adenocarcinoma cells after stimulation with interleukin-1.
Human pancreatic cancer is today an almost incurable disease with a 5-year survival rate of <5%. Chronic inflammation in the tumor region is often associated with cancer progression. In pancreatic tumors, the pro-inflammatory cytokine IL-1 has been found to affect the development of chemoresistance in this cancer type. In a search for new therapeutic targets we investigated the effect of this pro-inflammatory mediator on pancreatic cancer protein expression. Therefore, the human pancreatic adenocarcinoma cell line Colo357 was subjected to proteomic analysis after stimulation with IL-1 using 2D gel electrophoresis and mass spectrometry. We detected 11 spots as being differentially expressed after stimulation with IL-1 representing 11 different proteins. Among them, nicotinamide phosphoribosyltransferase (NAMPT) and prostaglandin H2 synthase 2 (PGHS-2) are crucial proteins whose expression in Colo357 is increased by IL-1. This study is the first one demonstrating an up-regulation of NAMPT in a tumor model for human pancreatic cancer. Several clinical trials using selective PGHS-2 or NAMPT inhibitors alone did not lead to an improvement in clinical outcome. Against the background of a high cardiovascular risk associated with PGHS-2-specific pharmacological inhibitors, we recommend a combinatory treatment with selective NAMPT and PGHS-2 inhibitors. This might overcome the limitations associated with PGHS-2 inhibitors since agents at low doses and with complementary mechanisms will be used. Such combined administration should positively affect the balance between risk and benefit in fighting the interplay of tumor-associated pancreatic inflammation and carcinogenesis in high-risk patients with pancreatic neoplasia.
Bauer
Lukas
L
Institut für Medizinische Biochemie und Molekularbiologie, Ernst-Moritz-Arndt-Universität, Greifswald, Germany.
Venz
Simone
S
Junker
Heike
H
Brandt
Rowena
R
Radons
Jürgen
J
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D015854:Up-Regulation
D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human