NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation

Abstract

Ionizing radiation (IR) causes not only acute tissue damage, but also late effects in several cell generations after the initial exposure. The thyroid gland is one of the most sensitive organs to the carcinogenic effects of IR, and we have recently highlighted that an oxidative stress is responsible for the chromosomal rearrangements found in radio-induced papillary thyroid carcinoma. Using both a human thyroid cell line and primary thyrocytes, we investigated the mechanism by which IR induces the generation of reactive oxygen species (ROS) several days after irradiation. We focused on NADPH oxidases, which are specialized ROS-generating enzymes known as NOX/DUOX. Our results show that IR induces delayed NADPH oxidase DUOX1-dependent H 2 O 2 production in a dose-dependent manner, which is sustained for several days. We report that p38 MAPK, activated after IR, increased DUOX1 via IL-13 expression, leading to persistent DNA damage and growth arrest. Pretreatment of cells with catalase, a scavenger of H 2 O 2 , or DUOX1 down-regulation by siRNA abrogated IR-induced DNA damage. Analysis of human thyroid tissues showed that DUOX1 is elevated not only in human radio-induced thyroid tumors, but also in sporadic thyroid tumors. Taken together, our data reveal a key role of DUOX1-dependent H 2 O 2 production in long-term persistent radio-induced DNA damage. Our data also show that DUOX1-dependent H 2 O 2 production, which induces DNA double-strand breaks, can cause genomic instability and promote the generation of neoplastic cells through its mutagenic effect.ionizing radiation | oxidative stress | NADPH oxidase | thyroid |

Radiation exposure and thyroid cancer: a review

“…The thyroid tissue contains a high quantity of NADPH oxidases, which are specialized ROS-generating enzymes that are known as NOX/ DUOX. Radiation exposure increases DUOX1 expression, leading to an important production of ROS in the thyroid gland after radiation exposure, and this may explain its high sensitivity to radiation (33). This DNA damage includes single-or double-strand breaks that will result in deletions and chromosomal rearrangements.…”

The immune network in thyroid cancer

“…This mechanism might be responsible for genetic instability and emergence of neoplastic clones in TC. 15 IL-10 is a pleiotropic cytokine, which can favor a shift toward Th2 response in the tumor microenvironment. 16 TAMs release IL-10, 13 and tumor cells themselves also produce IL-10.…”

NADPH oxidase in brain injury and neurodegenerative disorders

“…Recently, investigations on the DUOX enzymes have expanded to other body systems. DUOX1 has been reported to mediate allergic asthma [121], prolong ROS generation after irradiation [122], and play a role in cancer development [123]. DUOX2 has been reported to mediate keratinocyte inflammation [124], cochlear injury [103], and lung injury [125].…”