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Author Zheng, Hao ♦ Li, Ying ♦ Wang, Yuzhong ♦ Zhao, Haixia ♦ Zhang, Jing ♦ Chai, Hongyan ♦ Tang, Tian ♦ Yue, Jiang ♦ Guo, Austin M. ♦ Yang, Jing
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ARACHIDONIC ACID ♦ DMSO ♦ ENZYMES ♦ FLAVONOIDS ♦ HEAD ♦ HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ♦ HUMAN POPULATIONS ♦ IN VITRO ♦ IN VIVO ♦ LUNGS ♦ MAMMARY GLANDS ♦ MESSENGER-RNA ♦ METASTASES ♦ METHACRYLATES ♦ PROSTAGLANDINS ♦ RECEPTORS ♦ SECRETION ♦ SIGNALS ♦ THERAPY
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 E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr{sup 458}), phospho-PDK (Ser{sup 241}) and phospho-Akt (Thr{sup 308}). Conversely, the exogenous addition of PGE{sub 2}, 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 PGE{sub 2}, 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 PGE{sub 2}, 20-HETE and phospho-Akt (Thr{sup 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. - Highlights: • Isoliquiritigenin induces anoikis and suppresses metastasis in breast cancer. • COX-2 and CYP4A signaling plays crucial roles in isoliquiritigenin-induced anoikis. • PI3K/Akt deactivation is asssociated with isoliquiritigenin-induced anoikis. • Isoliquiritigenin is a promising multi-target agent for therapy of breast cancer.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2014-10-01
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 280
Issue Number 1


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