Die Hemmung von Hämoxygenase-1 (HO-1) sensibilisiert Pankreaskarzinomzellen für Chemo- und Radiotherapie

Abstract

Introduction: Pancreatic cancer shows very poor survival rates mainly due to its aggressive growth behavior and its exceptional resistance to all forms of anti-cancer treatment. The so-called protective gene heme oxygenase-1 (HO-1), which plays a key role in the defense against all kind of cellular stress, is highly expressed in different human cancers. In several experimental solid tumor models, inhibition of HO-1 activity decreased tumor growth, by induction of apoptosis and/or inhibition of angiogenesis. Its anti-oxidative and anti-apoptotic activity implies that HO-1 may promote radio- and chemoresistance of pancreatic cancer cells. Aim and methods: To determine the role of HO-1 in pancreatic cancer 27 human pancreatic cancer samples were analyzed in comparison to normal pancreatic tissue by quantitative PCR, Western blot analysis and confocal microscopy. The influence of radio- and chemotherapy on HO-1 expression in pancreatic cancer cell lines was evaluated. Furthermore, HO-1 expression was specifically suppressed by siRNA transfection. Alterations of growth behavior and resistance to anti-cancer treatment, such as radio- and chemotherapy were tested. Results: All of the pancreatic cancer samples showed significant over-expression of HO-1 (6-fold, p < 0.05) in comparison to normal pancreas on mRNA and protein level. The cancer tissue revealed marked immunoreactivity in tumor cells and in tumor associated immunocytes. Pancreatic cancer cell lines demonstrated divergent expression levels, from high to not detectable. Treatment of the pancreatic cancer cell lines with Gemcitabine or radiation strongly induced HO-1 expression (2- to 9-fold). Targeted knockdown of this HO-1 expression led to pronounced growth inhibition of the pancreatic cancer cells and made tumor cells significantly more sensitive to radio- and chemotherapy (p < 0,05). Conclusions: HO-1 seems to provide a growth advantage to pancreatic cancer cells and to make them resistant against radio- and chemotherapy. Specific inhibition of HO-1 sensitizes the tumor cells to anti-cancer treatment and may therefore be a new adjuvant agent in the therapy of pancreatic cancer.