Downregulation of COX-2 and CYP 4A Signaling by Isoliquiritigenin Inhibits Human Breast Cancer Metastasis Through Preventing Anoikis Resistance, Migration and Invasion

Authors

Hao Zheng, Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
Ying Li, Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
Yuzhong Wang, Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Haixia Zhao, Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
Jing Zhang, Animal Experimental Center of Wuhan University, Wuhan 430071, China.
Hongyan Chai, Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
Tian Tang, Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Jiang Yue, Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
Austin M. Guo, Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China; Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. Electronic address: Austin_Guo@nymc.edu.
Jing Yang, Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China. Electronic address: yangjingliu2013@163.com.

Author Type(s)

Faculty

DOI

10.1016/j.taap.2014.07.018

Journal Title

Toxicology and Applied Pharmacology

First Page

10

Last Page

20

Document Type

Article

Publication Date

10-1-2014

Keywords

Anoikis, Breast cancer, COX-2, CYP 4A, Isoliquiritigenin, Metastasis

Disciplines

Medicine and Health Sciences

Abstract

Flavonoids exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E2 (PGE2) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr(458)), phospho-PDK (Ser(241)) and phospho-Akt (Thr(308)). Conversely, the exogenous addition of PGE2, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted the in vitro anti-migratory and anti-invasive activities, whereas the addition of PGE2, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed the in vitro anti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited the in vivo lung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE2, 20-HETE and phospho-Akt (Thr(308)). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasion via downregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities.

Recommended Citation

Zheng, H., Li, Y., Wang, Y., Zhao, H., Zhang, J., Chai, H., Tang, T., Yue, J., Guo, A. M., & Yang, J. (2014). Downregulation of COX-2 and CYP 4A Signaling by Isoliquiritigenin Inhibits Human Breast Cancer Metastasis Through Preventing Anoikis Resistance, Migration and Invasion. Toxicology and Applied Pharmacology, 280 (1), 10-20. https://doi.org/10.1016/j.taap.2014.07.018