Inhibition of Heme Oxygenase-1 Increases Responsiveness of Pancreatic Cancer Cells to Anticancer Treatment

Abstract

Heme oxygenase-1 (HO-1) is believed to represent a key enzyme for the protection of cells against ''stress.'' Its overexpression in different types of human cancers supports the notion that HO-1 provides a growth advantage and contributes to cellular resistance against chemotherapy and radiotherapy. Given the poor survival rates of patients with pancreatic cancer due to its aggressive growth behavior and its exceptional resistance to all known forms of anticancer treatment, we have investigated the expression of HO-1 in human pancreatic cancer cells growth behavior and prognosis. Expression of HO-1 was analyzed in human pancreatic cancer samples in comparison with normal pancreas by quantitative PCR, Western blot, and confocal microscopy. The influence of radiotherapy and chemotherapy on HO-1 expression in pancreatic cancer cell lines was evaluated. Furthermore, HO-1 expression was specifically suppressed by small interfering RNA transfection and subsequently the alterations of growth behavior and resistance to anticancer treatment were tested. Human pancreatic cancer showed a 6-fold and 3.5-fold HO-1 up-regulation in comparison to normal pancreas based on mRNA and protein level, respectively (P < 0.05). Cancer tissues revealed marked HO-1 immunoreactivity in tumor cells and in tumor associated immunocytes. Treatment of the pancreatic cancer cell lines with gemcitabine or radiation strongly induced HO-1 expression. Targeted knockdown of HO-1 expression led to pronounced growth inhibition of the pancreatic cancer cells and made tumor cells significantly more sensitive to radiotherapy and chemotherapy. Therefore, specific inhibition of HO-1 expression may be a new option in pancreatic cancer therapy and may be used as sensitizer to chemotherapy and radiotherapy.

Inhibition of Heme Oxygenase-1 Interferes with the Transforming Activity of the Kaposi Sarcoma Herpesvirusencoded G Protein-coupled Receptor

“…This interesting finding is in line with a recent study showing that as a result of the oncogenic activity of the BCR/Abl chimera, leukemic cells from patients with myeloid leukemia display elevated expression levels of HO-1 (50). Similarly, pancreatic cancer presents a higher index of mutated Ras (31) and HO-1 overexpression (32,51). Although a direct correlation between Ras and HO-1 has not been studied, our preliminary results suggest that HO-1 is also partially required for activated Ras to induce transformation further supporting a possible more common role for HO-1 in tumorigenesis.…”

“…7A). Very recently and during the time our work was in progress, similar results have been shown in a model of pancreatic cancer where RNA interference of HO-1 led to pronounced growth inhibition of the pancreatic cancer cells and made tumor cells significantly more sensitive to radiotherapy and chemotherapy (32). Even more striking was the effect of the HO-1 inhibitor SnPP, as animals treated with this compound showed a remarkable reduction in vGPCR-induced tumor growth (Figs.…”

“…This effect was so marked that led us to investigate whether SnPP affected specifically vGPCR-induced foci or had an effect on transformation induced by other oncogenes. For example, although a direct correlation between a classical oncogene like Ras and HO-1 has not been reported, pancreatic cancers have a high incidence of Ras mutations (31) and HO-1 overexpression (32). Thus, we transfected NIH3T3 cells with an activated form of Ras (Ras V12) and scored foci formation after 2 weeks.…”

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

“…In our study, there was low efficiency of Runx2 silencing, although the current protocol used for siRNA transfection has been used for other genes (Berberat et al, 2005;Erkan et al, 2005;Kayed et al, 2005). Furthermore, two additional Runx2 siRNA sequences were used, and these exhibited even lower silencing efficiencies than the one that was used in the final experiments.…”

Enhancement of parthenolide-induced apoptosis by a PKC-alpha inhibition through heme oxygenase-1 blockage in cholangiocarcinoma cells

“…Suppression or silencing of HO-1 resulted in increased susceptibility of tumor cells to PTL. Similarly, specific inhibition of HO-1 expression increases the response of pancreatic cancer to anticancer treatment and enhances the cytotoxic effect of gemcitabine in urothelial cancer cells (Berberat et al, 2005;Miyake et al, 2010). Futhermore, PKC inhibition sensitizes TNFα-or TRAIL-induced apoptosis in cancer cells (Nishida et al 2003;Shi et al, 2005).…”