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The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia
Author(s) -
Oh Se-Hyun,
Choi Soon-Youn,
Choi Hyo-Jung,
Ryu Hye-Myung,
Kim You-Jin,
Jung Hee-Yeon,
Cho Jang-Hee,
Kim Chan-Duck,
Park Sun-Hee,
Kwon Tae-Hwan,
Kim Yong-Lim
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802415rr
Subject(s) - cancer research , metastasis , breast cancer , mapk/erk pathway , chemistry , cell migration , cancer , medicine , reactive oxygen species , endocrinology , cell , kinase , biochemistry
Hypercholesterolemia is reported to increase reactive oxygen species (ROS) and to promote breast cancer progression. ROS play an important role in tumor biology, and xanthine oxidase (XO) is an enzyme that generates ROS. The effects of febuxostat (FBX), an XO inhibitor, on breast cancer cell migration under LDL stimulation in vitro and metastasis of breast cancer associated with hypercholesterolemia in vivo were studied. In vitro , FBX significantly inhibited LDL‐induced ROS production and cell migration. Treatment of small interfering RNA against XO was consistent with the findings of FBX treatment. In vivo , a significant increase of tumor growth and pulmonary metastasis was observed in a xenograft mouse model with 4T1 cells on a high cholesterol diet (HCD), both of which were markedly inhibited by FBX or allopurinol treatment. Moreover, ERK represented the main target‐signaling pathway that was affected by FBX treatment in a xenograft mouse model on an HCD evaluated by NanoString nCounter analysis. Consistently, MEK/ERK inhibitors directly decreased the LDL‐induced cell migration in vitro . In conclusion, FBX mitigates breast cancer cell migration and pulmonary metastasis in the hyperlipidemic condition, associated with decreased ROS generation and MAPK phosphorylation. The inhibition of ERK pathways is likely to underlie the XO inhibitor‐mediated suppression of breast cancer cell migration.—Oh, S.‐H., Choi, S.‐Y., Choi, H.‐J., Ryu, H.‐M., Kim, Y.‐J., Jung, H.‐Y., Cho, J.‐H., Kim, C.‐D., Park, S.‐H., Kwon, T.‐H., Kim, Y.‐L. The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia. FASEB J. 33, 7301–7314 (2019). www.fasebj.org