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NADPH oxidase 1 activity and ROS generation are regulated by Grb2/Cbl-mediated proteasomal degradation of NoxO1 in colon cancer cells

Title
NADPH oxidase 1 activity and ROS generation are regulated by Grb2/Cbl-mediated proteasomal degradation of NoxO1 in colon cancer cells
Authors
Joo J.H.Oh H.Kim M.An E.J.Kim R.-K.Lee S.-Y.Kang D.H.Kang S.W.Park C.K.Kim H.Lee S.-J.Lee D.Seol J.H.Bae Y.S.
Ewha Authors
배윤수강상원이대기주정희강동훈
SCOPUS Author ID
배윤수scopus; 강상원scopus; 이대기scopus; 주정희scopusscopus; 강동훈scopus
Issue Date
2016
Journal Title
Cancer Research
ISSN
0008-5472JCR Link
Citation
vol. 76, no. 4, pp. 855 - 865
Publisher
American Association for Cancer Research Inc.
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
The generation of reactive oxygen species (ROS) is required for proper cell signaling, but must be tightly regulated to minimize deleterious oxidizing effects. Activation of the NADPH oxidases (Nox) triggers ROS production and, thus, regulatory mechanisms exist to properly control Nox activity. In this study, we report a novel mechanism in which Nox1 activity is regulated through the proteasomal degradation of Nox organizer 1 (NoxO1). We found that through the interaction between NoxO1 and growth receptor-bound protein 2 (Grb2), the Casitas B-lineage lymphoma (Cbl) E3 ligase was recruited, leading to decreased NoxO1 stability and a subsequent reduction in ROS generation upon epidermal growth factor (EGF) stimulation. Additionally, we show that EGF-mediated phosphorylation of NoxO1 induced its release from Grb2 and facilitated its association with Nox activator 1 (NoxA1) to stimulate ROS production. Consistently, overexpression of Grb2 resulted in decreased Nox1 activity, whereas knockdown of Grb2 led to increased Nox1 activity in response to EGF. CRISPR/Cas9-mediated NoxO1 knockout in human colon cancer cells abrogated anchorage-independent growth on soft agar and tumor-forming ability in athymic nude mice. Moreover, the expression and stability of NoxO1 were significantly increased in human colon cancer tissues compared with normal colon. Taken together, these results support a model whereby Nox1 activity and ROS generation are regulated by Grb2/Cbl-mediated proteolysis of NoxO1 in response to EGF, providing new insight into the processes by which excessive ROS production may promote oncogenic signaling to drive colorectal tumorigenesis. © 2016 American Association for Cancer Research.
DOI
10.1158/0008-5472.CAN-15-1512
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자연과학대학 > 생명과학전공 > Journal papers
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