NADPH oxidases and cancer

Abstract

The mechanism by which reactive oxygen species (ROS) are produced by tumour cells remained incompletely understood until the discovery over the last 15 years of the family of NADPH oxidases (NOXs 1-5 and dual oxidases DUOX1/2) which are structural homologues of gp91phox, the major membrane-bound component of the respiratory burst oxidase of leucocytes. Knowledge of the roles of the NOX isoforms in cancer is rapidly expanding. Recent evidence suggests that both NOX1 and DUOX2 species produce ROS in the gastrointestinal tract as a result of chronic inflammatory stress; cytokine induction (by interferon-γ, tumour necrosis factor α, and interleukins IL-4 and IL-13) of NOX1 and DUOX2 may contribute to the development of colorectal and pancreatic carcinomas in patients with inflammatory bowel disease and chronic pancreatitis, respectively. NOX4 expression is increased in pre-malignant fibrotic states which may lead to carcinomas of the lung and liver. NOX5 is highly expressed in malignant melanomas, prostate cancer and Barrett's oesophagus-associated adenocarcinomas, and in the last it is related to chronic gastro-oesophageal reflux and inflammation. Over-expression of functional NOX proteins in many tissues helps to explain tissue injury and DNA damage from ROS that accompany pre-malignant conditions, as well as elucidating the potential mechanisms of NOX-related damage that contribute to both the initiation and the progression of a wide range of solid and haematopoietic malignancies.

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

“…Different types of cancer cells appear to produce higher levels of ROS than their normal counterparts [7,8]. For example, early reports described enhanced ROS production in RAS-transformed fibroblasts [9], a finding which has later been corroborated in human CD34-positive hematopoietic progenitor cells [10].…”

The Janus-Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts

“…Seven isoforms have been identified to produce ROS, among which NOX-4 produces H 2 O 2 and NOX-1, NOX-2, and NOX-5 generate O 2 ∙− [79]. In conditions evoking chronic inflammation, which is the case of cachexia, high amounts of ROS originating from NOX could negatively influence gastrointestinal and pancreatic cancer development [80]. Clinically, the expression of NOX-1 and NOX-4 in tumor was associated with poor survival and cancer relapse [81, 82].…”

“…Clinically, the expression of NOX-1 and NOX-4 in tumor was associated with poor survival and cancer relapse [81, 82]. Another isoform, NOX-5, was also found to be overexpressed in numerous cancers, including colon, melanoma, breast, lung, and prostate cancer [80]. However, the role of NOX in cancer and cancer cachexia has not been addressed in depth clinically and further studies are needed to establish its exact role.…”

Psoralidin induced reactive oxygen species (ROS)-dependent DNA damage and protective autophagy mediated by NOX4 in breast cancer cells

“…NADPH oxidase (NOXs), one of the main ROS sources in biological systems, plays important roles in cancer chemotherapy. There are 7 members of NOXs including NOXs 1-5 and dual oxidases DUOX1/2 ( Meitzler et al 2014;Roy et al 2015 ). Among these members, recent attention has been paid to the role of NOX4 in cancer ( Guo and Chen 2015 ).…”