Pancreatic ductal adenocarcinoma (PDAC) is a serious gastroenteric cancer disease with poor prognosis. In recent years, its morbidity rate and death rate have significantly increased with a rapid rise in the number of PDAC cases. The death rate of PDAC has reached 90% with a five-year survival rate of less than 1%, and the average survival time for patients who cannot undergo surgery is six months.
The activation of Kras and the inactivation of p16 are the most frequently identified genetic alterations in PDAC. Previous studies show that the mutational activation of Kras has been detected in over 90% of PDAC cases, and mutational inactivation of the p16INK4a (hereafter referred to as p16) tumor suppressor gene can be identified in 50%-70% of PDAC cases.
Recently, Prof. Ruihua Xu’s team and Prof. Peng Huang’s team of Sun Yat-sen University Cancer Center, together with Prof. Paul J. Chiao’s team of MD Anderson Cancer Center found that mutant Kras and the silencing of KrasG12V-induced p16 expression in human pancreatic epithelial cells (HPNE or HPDE), which resulted in increased glycolytic activity and malignant transformation both in vitro and in vivo.
In their study, they unequivocally demonstrated that NOX4 activity was induced both through transcriptional upregulation of p22phox expression via oncogenic Kras-activated NF-B, and through increased NOX4 overexpression by loss of the p16-regulated Rb-E2F pathway.
Furthermore, they showed that elevated NOX4 activity accelerates oxidation of NADH and supports increased glycolysis by generating NAD+, a substrate for GAPDH-mediated glycolytic reaction, promoting PDAC development.
Both alterations are also detectable in PDAC cell lines, transgenetic mice tissues and patient specimens. Genetic suppression of NOX4 expression or pharmacologic targeting of NOX4 using DPI, leads to metabolic disruption and prolongs transgenetic iKras; p53L/+ mice survival.
The research is published online in the Journal of Nature Communications (2017 Feb 24;8:14437). The research discovers NOX4 is a potential therapeutic target for PDAC and provides a biochemical explanation for the cooperation between p16 inactivation and Kras activation in reprogramming energy metabolism and PDAC development.
Prof. Ruihua Xu's research team
Written by Prof. Huaiqiang Ju, Department of Experiential Research, Sun Yat-sen University Cancer Center