Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion

Journal Article · Wed Oct 01 04:00:00 EDT 2014 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2014.07.018· OSTI ID:22439847

Zheng, Hao; Li, Ying ^[1]; Wang, Yuzhong ^[2]; Zhao, Haixia ^[1]; Zhang, Jing ^[3]; Chai, Hongyan ^[4]; Tang, Tian ^[5]; Yue, Jiang ^[1]; Yang, Jing ^[1]

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1. Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)
2. Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079 (China)
3. Animal Experimental Center of Wuhan University, Wuhan 430071 (China)
4. Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China)
5. Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China)

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.

• OSTI ID: 22439847
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 280; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 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