Nicotinamide phosphoribosyltransferase and prostaglandin H2 synthase 2 are up-regulated in human pancreatic adenocarcinoma cells after stimulation with interleukin-1

Abstract

Abstract. 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 proinflammatory 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 H 2 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. IntroductionPancreatic cancer is the fourth cause of cancer-related mortality in the USA and the sixth one in Europe with more than 250,000 patients estimated to die of the disease worldwide (1). This cancer entity is one of the most deadly of all malignancies with a death to incidence ratio approaching one making mortality rate a robust approximation of incidence for pancreatic cancer (2). The incidence of pancreatic cancer correlates with increasing age reaching a peak in the 65-75-years old age group (3). Approximately three-fourths of patients will die within one year of diagnosis and <5% survive up to 5 years after diagnosis (4). The poor outcome of pancreatic cancer is reflected by non-resectable primary lesions, locally advanced tumors, and a high metastatic potential (5). Since only a few patients benefit from classical adjuvant chemo-and radiotherapy, complete surgical resection is the superior treatment modality for patients with resectable disease. Unfortunately, the majority of pancreatic cancer patients present with locally advanced or metastatic tumors are not amenable for curative surgery. Only a disappointing 15% of patients at the time of diagnosis are eligible to undergo surgical excision, and even patients who have undergone such curative resection often die of recurrent carcin...