Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels

Bo Kong,Mert Erkan,Christoph W Michalski,Chengjia Qia,Jörg Kleeff

doi:10.3389/fphys.2013.00246

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease without clearly known disease causes. Recent epidemiological and animal studies suggest that the supplementation of dietary antioxidants (e.g., vitamins C and E) decreases cancer risk, implying that increased reactive oxygen species (ROS) may play a role in pancreatic carcinogenesis. However, oncogenic Kras mutations (e.g., KrasG12D), which are present in more than 90% of PDAC, have been proven to foster low intracellular ROS levels. Here, oncogenic Kras activates expression of a series of anti-oxidant genes via Nrf2 (nuclear factor, erythroid derived 2, like 2) and also mediates an unusual metabolic pathway of glutamine to generate NADPH. This can then be used as the reducing power for ROS detoxification, leading collectively to low ROS levels in pancreatic pre-neoplastic cells and in cancer cells. In adult stem cells and cancer stem cells, low ROS levels have been associated with the formation of a proliferation-permissive intracellular environment and with perseverance of self-renewal capacities. Therefore, it is conceivable that low intracellular ROS levels may contribute significantly to oncogenic Kras-mediated PDAC formation.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor entity without clearly known disease causes (Kong et al, 2011; Siegel et al, 2013)
Recent epidemiological and animal studies suggest that the supplementation of dietary antioxidants decreases cancer risk, implying that increased reactive oxygen species (ROS) may play a role in pancreatic carcinogenesis
Recent studies have demonstrated that oncogenic KrasG12D mediates activation of metabolic programs, which effectively detoxify ROS and reduce ROS levels in pancreatic pre-neoplastic cells and in cancer cells

Summary

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor entity without clearly known disease causes (Kong et al, 2011; Siegel et al, 2013). Collaboration between Nrf2-mediated ROS detoxification and the NADPH-generating metabolic program collectively contributes to a “reduced” intracellular environment (e.g., low ROS levels) Since both of these depend on the activity of oncogenic Kras, it is conceivable that such an intracellular environment constitutes an important step in pancreatic carcinogenesis. THE TUMOR-SUPPRESSING FUNCTION OF ANTIOXIDANTS DOES NOT CONTRADICT TUMOR-PROMOTING EFFECTS OF ONCOGENIC Kras-MEDIATED LOW INTRACELLULAR ROS LEVELS As earlier illustrated, prospective studies have suggested an association between dietary antioxidants and a decreased risk for developing pancreatic cancer (Gong et al, 2010; Banim et al, 2012; Heinen et al, 2012). Further studies are required to clarify how/why antioxidants execute their tumor-suppressor functions on oncogenic Kras-mediated low intracellular ROS levels in the pancreas

LOW ROS LEVELS IN DIFFERENT BIOLOGICAL SYSTEMS

Biological significance

CONCLUSION

Findings

Mutagenicity and repair of oxidative