title: The role of 15-Lipoxygenase-1 in pancreatic carcinogenesis
creator: Noor, Seema
subject: 610
subject: 610 Medical sciences Medicine
description: The results from epidemiological and animal studies suggest that a high  fat consumption  is associated with an increased incidence and growth of tumors at several specific organ sites, including pancreas, colon, breast and prostate. Recently, the important role of lipoxygenase pathways in fat metabolism and in the regulation of pancreatic cancer  cell proliferation and survival was identified. The arachidonic and linoleic acid metabolizing 15-lipoxygenase-1 (15-LOX-1) acts anti-tumorigenic in colon, esophageal and gastric cancers. However, since nothing is known about 15-LOX-1 in pancreatic cancer, this was investigated in the present study. Expression of 15-LOX-1 was investigated by RT-PCR and western blotting in human pancreatic cancer cell lines and by immunohistochemistry in human pancreatic cancer tissues. Cell proliferation was analyzed in 15-LOX-1 overexpressing pancreatic tumor cell lines and after treatment with both the substrates and products. Restored 15-LOX-1 expression after sodium butyrate treatment was analyzed by western blot analysis. RT-PCR and western blotting showed absence or very weak expression of 15-LOX-1 in all pancreatic cancer cell lines tested. 15-LOX-1 was strongly stained in normal ductal cells, tubular complexes and centroacinar cells, but no staining was seen in islets, cancer cells, PanIN lesions, or in tumor cells in lymph node metastases. Over-expression of 15-LOX-1 in pancreatic tumor cells or treatment with its downstream metabolite 15-S-HETE resulted in decreased cell growth whereas 13-S-HODE did not result in any altered proliferation. Treatment with the substrate AA reduced cell proliferation significantly though no effect was observed after LA treatment. On cell cycle progression level no difference between 15-LOX-1 expressing and mock cells was detectable. Though a clear increase in apoptosis was detected in 15-LOX-1 over-expressing cells. A re-establishment of 15-LOX-1 in pancreatic tumor cell lines could be affirmed on protein level, further sodium butyrate incubation resulted in a strong regression of cell proliferation. Additionally, NaBu incubation restored expression of the anti-apoptotic protein KAI1 whereas no effect on protein expression level was detectable for the pro-metastatic protein S100A4. This study shows that expression of the anti-tumorigenic 15-LOX-1 is suppressed in pancreatic cancer and already in PanINs. These findings provide evidence that loss of      15-LOX-1 may play an important role in pancreatic carcinogenesis, possibly as a tumor suppressor gene. Lipoxygenases are attractive targets for the prevention and treatment of pancreatic cancer. Induction of 15-LOX-1 expression should be harmless for normal cells and, therefore, may be a valuable new anti-tumorigenic tool in the fight against pancreatic cancer. 
date: 2007
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/7689/1/Binder_Seema.pdf
identifier: DOI:10.11588/heidok.00007689
identifier: urn:nbn:de:bsz:16-opus-76893
identifier:   Noor, Seema  (2007) The role of 15-Lipoxygenase-1 in pancreatic carcinogenesis.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/7689/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: ger