Targeting reactive oxygen species in development and progression of pancreatic cancer

Abstract

Introduction Pancreatic ductal adenocarcinoma (PDA) is characterized by expression of oncogenic KRas which drives all aspects of tumorigenesis. Oncogenic KRas induces the formation of reactive oxygen species (ROS) which have been implicated in initiation and progression of PDA. To facilitate tumor promoting levels and to avoid oncogene-induced senescence or cytotoxicity, ROS homeostasis in PDA cells is balanced by additional up-regulation of antioxidant systems. Areas Covered We examine the sources of ROS in PDA, the mechanisms by which ROS homeostasis is maintained, and the biological consequences of ROS in PDA. Additionally, we discuss the potential mechanisms for targeting ROS homoeostasis as a point of therapeutic intervention. An extensive review of the relevant literature as it relates to the topic was conducted using PubMed. Expert Commentary Even though oncogenic mutations in the KRAS gene have been detected in over 95% of human pancreatic adenocarcinoma, targeting its gene product, KRas, has been difficult. The dependency of PDA cells on balancing ROS homeostasis could be an angle for new prevention or treatment strategies. These include use of antioxidants to prevent formation or progression of precancerous lesions, or methods to increase ROS in tumor cells to toxic levels.

Mitochondrial and Oxidative Stress-Mediated Activation of Protein Kinase D1 and Its Importance in Pancreatic Cancer

“…This opens an opportunity for targeting tumor cells (46). In response to ROS, PKD1 has been shown to regulate prosurvival and proliferation signaling through various factors (Figure 2).…”

Selenoproteins and Metastasis

“…EMT via anchorage independent growth properties of mouse lung carcinoma (LLC1) cells in vitro and in mice injected with these cells was reduced using RNAi techniques targeting TXNRD1 (Yoo, et al, 2006). In fact, EMT has become a focus of TXNRD1 inhibitors as a potential therapeutic strategy for reducing metastasis (Durand and Storz, 2017). TXNRD2 has been less studied, but this selenoenzyme was upregulated in metastatic osteosarcoma and the TXNRD inhibitor, auranofin, was found to reduce metastasis to pulmonary tissues (Topkas et al, 2016).…”

Superoxide Dismutases in Pancreatic Cancer

“…Mutation of K- ras alone is enough to induce tumorigenicity in previously non-tumorigenic, immortalized pancreas cells [ 43 ] Tumorigenesis from K-ras mutation follows a predictable progression from acinar cells to a progenitor ductal phenotype and, finally, to the early pancreatic intra-epithelial neoplasm (PanIN) [ 44 , 45 , 46 ]. The point mutation of the K- ras oncogene is a common event in the early development of pancreatic cancer leading to an overall increase in production of reactive oxygen species via activation of NOX [ 3 ]. Interestingly, fibroblasts transfected with the viral ras oncogene have a resulting increase in O 2 ●− production that has been proposed to act as a second messenger molecule to promote cell proliferation [ 47 ].…”

“…Therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy is poor, resulting in a dismal 5-year survival of less than 3% [ 2 ]. Mutation of the K- ras oncogene is a common event in the early development of pancreatic cancer occurring in 95% of pancreatic cancers, with a resulting overall increase in production of reactive oxygen species (ROS) [ 3 ]. Superoxide dismutases (SODs) modulate the oxidative status of the cell by dismutation of two molecules of O 2 ●− into hydrogen peroxide (H 2 O 2 ) and molecular oxygen (O 2 ) [ 4 ].…”