Roles of DNA repair enzyme OGG1 in innate immunity and its significance for lung cancer

Abstract

Cytokines are pivotal mediators of the immune response, and their coordinated expression protects host tissue from excessive damage and oxidant stress. Nevertheless, the development of lung pathology, including asthma, chronic obstructive pulmonary disease, and ozone-induced lung injury, is associated with oxidant stress; as evidence, there is a significant increase in levels of the modified guanine base 7,8-dihydro-8-oxoguanine (8-oxoG) in the genome. 8-OxoG is primarily recognized by 8-oxoguanine glycosylase 1 (OGG1), which catalyzes the first step in the DNA base excision repair pathway. However, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, including NF-κB, to their cognate sites to enable expression of cytokines and chemokines, with ensuing recruitments of inflammatory cells. Hence, defective OGG1 will modulate the coordination between innate and adaptive immunity through excessive oxidant stress and cytokine dysregulation. Both oxidant stress and cytokine dysregulation constitute key elements of oncogenesis by KRAS, which is mechanistically coupled to OGG1. Thus, analysis of the mechanism by which OGG1 modulates gene expression helps discern between beneficial and detrimental effects of oxidant stress, exposes a missing functional link as a marker, and yields a novel target for lung cancer.

The Combination of Astragalus membranaceus and Angelica sinensis Inhibits Lung Cancer and Cachexia through Its Immunomodulatory Function

“…The excessive production of free radicals would cause oxidative stresses, which generally activate transcription factors such as NF- κ B, STAT3, HIF-1 α , and AP-1 [37]. ROS and NF- κ B are both involved in 7,8-dihydro-8-oxoguanine (8-oxoG) and KRAS -mediated inflammation, oncogenesis, and the relative interaction between innate and adaptive immunity [38]. In neoplasms, inordinate NF- κ B promote the expression of many vital modulators of cancer progression, such as HIF-1 α , AP-1, STAT3, and MUC1 [39].…”

Plausible Role of Estrogens in Pathogenesis, Progression and Therapy of Lung Cancer

“…Published data suggest that there is an increased risk of lung cancer in smokers with low OGG1 activity [ 8 ]. Tobacco smoke contains over 60 carcinogens, including aromatic hydrocarbons such as nitrosamines and benzopyrene, carbon monoxide (chad), tar, phenol, cresol, formaldehyde and hydrogen cyanide [ 10 , 11 , 12 ]. Polycyclic aromatic hydrocarbons activated by cytochrome P450 enzymes can bind to DNA [ 10 , 11 , 12 ].…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…133,134 Consistently, the activity of UPS was increased when autophagy was inhibited by chemical agents or by small interfering RNAs targeting autophagy-related genes. [141][142][143] As a mechanism of negative feedback regulation, the IjBa gene is expressed by activated NF-jB. When proteasome activity is impaired, its substrates may be imported into mitochondria to be degraded by mitophagy.…”

“…139,140 DNA damaging agents increase the activity of NF-jB, both by increased recruitment to chromatin, as well as by increased interaction with protein complexes that recruit RNA polymerase II. [141][142][143] As a mechanism of negative feedback regulation, the IjBa gene is expressed by activated NF-jB. 144,145 To sustain NF-jB activity in some cells, inhibition of the proteasome may induce proteolysis of IjBa by the lysosome, and inhibition of the lysosome can induce proteolysis of IjBa by calpain.…”