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

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.

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

“…Nrf2 induces expression of many cytoprotective proteins responsible for maintaining cellular redox stability. Recent study also showed that nuclear Nrf2 expression play an important role in ROS detoxification during pancreatic carcinogenesis (29), and is related to a poor survival in patients with pancreatic adenocarcinoma (30). Western blot analysis showed that the expression of Nrf2-targeting antioxidants such as SOD1, GPX, GST-Pi, GCLC, and GCLM, was increased following gemcitabine treatment.…”

Keap1–Nrf2 signalling in pancreatic cancer

“…Resulting damage from oxidative stress, if substantial, can lead to cell death unless adaptive processes are implemented that can withstand the harmful effects. ROS comprises oxygen-derived molecules and free radicals which can arise during normal metabolism (Turrens, 2003), and also during cell proliferation or abnormal and stressful events, such as endoplasmic reticulum (ER) stress or oncogenic transformation (Zhang and Kaufman, 2008;Logsdon and Ji, 2013;Kong et al, 2013). Moreover, exogenous toxic environmental agents, such as chemotherapy drugs and cigarette combustion products, may also induce free radicals (Hayes and McMahon, 2009;Ju et al, 2015).…”

Soluble factors from stellate cells induce pancreatic cancer cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification

“…The sustained Nrf2 signaling in AsPC-1 may be due to activating KRAS mutation [28]. Oncogenic KRAS is a key driver mutation in PDAC tumorigenesis [36] and is shown to render lower intracellular ROS levels by activating Nrf2 programs [37]. KRAS mutation is also essential in promoting glutaminolysis in PDAC to fuel anabolic processes in supporting cell growth [38, 39].…”