NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4

Abstract

There is an urgent need to identify vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). PDAC cells acquire metabolic changes that augment NADPH production and cytosolic redox homeostasis. Here, we show that high NADPH levels drive activity of NADPH oxidase 4 (NOX4) expressed in the endoplasmic reticulum (ER) membrane. NOX4 produces H2O2 metabolized by peroxiredoxin 4 (PRDX4) in the ER lumen. Using functional genomics and subsequent in vitro and in vivo validations, we find that PDAC cell lines with high NADPH levels are dependent on PRDX4 for their growth and survival. PRDX4 addiction is associated with increased reactive oxygen species, a DNA-PKcs–governed DNA damage response and radiosensitivity, which can be rescued by depletion of NOX4 or NADPH. Hence, this study has identified NOX4 as a protein that paradoxically converts the reducing power of the cytosol to an ER-specific oxidative stress vulnerability in PDAC that may be therapeutically exploited by targeting PRDX4.

Evolutionary and structural analyses of the NADPH oxidase family in eukaryotes reveal an initial calcium dependency

“…To date, several of their physiological functions include, but are not limited to, cell signalling, phagocyte function in innate immunity (NOX2), host defence (NOXA, RBOHs and NOX2), thyroid hormone synthesis (DUOXs), tolerance to stress and plant cell signaling (RBOHs), cell differentiation, mitogenic functions and cell proliferation and differentiation (NOX4, NOXB) [ [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] ]. Mutations affecting function of the human NOXs cause severe diseases such as chronic granulomatous disease (NOX2), and NOX dysregulation has been attributed to cardiovascular, neurological disorders (NOX2, NOX4), and pulmonary diseases and cancers (NOX1 and NOX4) [ [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] ].…”

Loss of Peroxiredoxin IV Protects Mice from Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development

“…The tumors in transgenic groups also had lower oxidative stress and higher macrophage infiltration. Furthermore, Prx4 has been suggested to promote progression of prostate cancer, pancreatic cancer, hepatocellular carcinoma and colorectal cancer [ 17 , 40 , 41 , 42 ]. Lastly, loss of Prx4 providing resistance to colitis fits the general trend observed when antioxidant enzymes are depleted in colitis models: loss of Prx1, Prx2, and Prx6 and the combined loss of GPx1 and catalase all improved colitis in mouse and rat models [ 43 , 44 , 45 , 46 ].…”

Comprehensive Analysis of the PRDXs Family in Head and Neck Squamous Cell Carcinoma

“…We also found that the upregulated PRDX4 might play an oncogene function in provoking proliferation, metastasis, and invasion, leading to a poor prognosis of HNSCC patients, which is confirmed in OSCC ( 14 ). The silencing of PRDX4 is related to the generation of ROS in the endoplasmic reticulum, which diffuses to the nucleus and induces DNA damage ( 30 ). In addition, PRDX4 can reduce the expression of adhesion molecules ( 31 ), thereby increasing the possibility of metastasis and invasion.…”