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Introduction: Pancreatic cancer is the fourth leading cause of cancer-related death. Because of late diagnosis and lack of therapeutic options it has an abysmal prognosis, with a median survival time of 6 months after diagnosis and less than 5% surviving five years. Obesity and high intake of ω-6 polyunsaturated fatty acid are identified as risk factors. Oxidative lipid metabolism, particularly the eicosanoid metabolism has been shown to play an important role in pancreatics tumor progression. Lipoxygenases (LOX) are key enzymes in the ecosanoid pathway and might be valuable as potential targets for early diagnosis, prevention and treatment of pancreatic cancer. It has been shown that 5- and 12 LOX exhibit pro-tumorigenic effects while 15-LOX-1 show anti-tumorigenic activities. In this study, the role of 15-LOX-2 in pancreatic tumor progression was investigated. Material and Methods: Expression profiling was performed in pancreatic cancer cells and normal and neoplastic human pancreatic tissues (23 normal pancreas from cadaver donors, 34 chronic pancreatitis, 30 pancreatic cancers, 26 IPMN) by RT-PCR, western blotting and immunohistochemistry. In order to analyze potential anti-tumorigenic effects, inducible and stably overexpessing 15-LOX pancreatic tumor cell lines were established. In addition, tumor cells were treated with 15-LOX metabolites 15-S-HETE and 13-S-HODE. Cell proliferation was detemined with cell counting and WST-1 assay. Cell cycle analysis was performed using FACS. Results: 15-LOX-1 and 15-LOX-2 are not expressed in all pancreatic cancer cell lines, tested. Expression of 15-LOX-1 was evident in normal ductal and centroacinar cells as well as in tubular complexes but was absent in preneoplastic lesions (PanINs) and in pancreatic cancer cells. Similar results could be demonstrated for 15-LOX-2 with significant over-expression in normal compared to malignant pancreatic tissues. This is indicating that expression of both 15-LOX isoforms is lost during tumor development. Forced expression of both 15-LOX isoforms or treatment with the metabolite 15-S-HETE resulted in significant inhibition of tumor cell proliferation and caused apoptosis. Unexpectedly, overexpression of a catalytically inactive 15-LOX-2 also reduced tumor cell growth, though to a lesser extent, indicating that at least some of the LOX-mediated effects are independent from enzymatic activity. Preliminary data suggest that expression of 15-LOX-2 correlates with a strong increase of p53. Conclusion: For the first time, expression of both 15-LOX-isoforms could be demonstrated in pancretic tissues. The data suggest that loss of both 15-LOX isoforms during pancreatic carcinogenesis may provide a growth advantage for the tumor cells. Therefore, restoration of 15-LOX-1 and 15-LOX-2 in pancreatic cancer could be a new strategy in treating patients with this dismal disease. |
