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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med Chin    2009, Vol. 3 Issue (1) : 1-7     DOI: 10.1007/s11684-009-0018-5
REVIEW |
NADPH oxidase and reactive oxygen species as signaling molecules in carcinogenesis
Gang WANG()
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA
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Abstract  

Reactive oxygen species (ROS) are small molecule metabolites of oxygen that are prone to participate in redox reactions via their high reactivity. Intracellular ROS could be generated in reduced nicotinamide-adenine dinucleotidephosphate (NADPH) oxidase-dependent and/or NADPH oxidase-independent manners. Physiologically, ROS are involved in many signaling cascades that contribute to normal processes. One classical example is that ROS derived from the NADPH oxidase and released in neurotrophils are able to digest invading bacteria. Excessive ROS, however, contribute to pathogenesis of various human diseases including cancer, aging, dimentia and hypertension. As signaling messengers, ROS are able to oxidize many targets such as DNA, proteins and lipids, which may be linked with tumor growth, invasion or metastasis. The present review summarizes recent advances in our comprehensive understanding of ROS-linked signaling pathways in regulation of tumor growth, invasion and metastasis, and focuses on the role of the NADPH oxidase-derived ROS in cancer pathogenesis.

Keywords free radicals      tumor      phox      cell proliferation      cancer therapy     
Corresponding Authors: WANG Gang,Email:gaw2001@med.cornell.edu   
Issue Date: 05 March 2009
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-009-0018-5     OR     http://academic.hep.com.cn/fmd/EN/Y2009/V3/I1/1
Fig.1  Metabolism of reactive oxygen species. is considered as the “primary” reactive oxygen species and mainly generated by the mitochondria, the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, the cyclooxygenase and the xanthine oxidase. On one hand, can rapidly react with NO to form highly reactive ONOO that can modify protein targets. On the other hand, is dismutated by superoxide dismutase (SOD) to HO, which has three major fates: (1) HO is most efficiently scavenged by catalase, as well as glutathione peroxidase (GPX), into HO; (2) HO is broken down by some transition metals to reactive hydroxyl radical (Fenton reaction), which plays an important role in DNA damage or lipid peroxidation; (3) HO is degraded by myeloperoxidase (MPO) to O and HO, generating HOCl in the presence of chloride (Cl).
Fig.2  Exemplified pathways for activation of the NOX2 NADPH oxidase. One example is the protein kinase C (PKC)-dependent pathway. PKC can phosphorylate the cytosolic regulatory subunit p47. The phosphorylated p47, along with other cytosolic subunits p40 and p67, translocate towards and binds to the plasma membrane-anchored gp91, the catalytic subunit of the NOX2 reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. This multi-subunit assembly leads to activation of the whole NOX2 NADPH oxidase system, resulting in the generation of reactive oxygen species (ROS). The NADPH oxidase also participates in signaling in response to various hormones and growth factors. A typical example is the response of the NOX2 NADPH oxidase to activation of the epidermal growth factor (EGF) receptor, where PIK, Akt and Rac1 signals are involved in ROS production.
enzymehighly expressed inregulator
NOX1colon epithelium, gastric pit, vascular smooth musclep22phox
NOX2 (gp91phox)phagocytes, lymphocytes, neurons, carotid body, kidney, vascular smooth musclep47phox, Rac1/2, PKC
NOX3fetal tissue and inner ear
NOX4fetal tissue, kidney, pancreas, ovary, testis, neuron
NOX5fetal tissue, spleen, lymphocytes, sperm glands, mammary glands, cerebrum, stomachcalcium
Tab.1  Distribution of human NADPH oxidases
Fig.3  The NADPH oxidase signaling pathways associated with carcinogenesis can be induced by chronic infection/inflammation or peptide growth factors. PKC: protein kinase C; ROS: reactive oxygen species; NADPH: reduced nicotinamide-adenine dinucleotide phosphate; EGF: epidermal growth factor; PDGF: platelet-derived growth factor; TNF: tumor necrosis factor; TGF: tumor growth factor; DPI: diphenyleneiodonium.
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