title: Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Animal Experimental Center of Wuhan University, Wuhan 430071, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Chai
authors.affiliation: Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
authors.affiliation: 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.
authors.forename: Austin M
authors.initials: AM
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China. Electronic address: yangjingliu2013@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D047188:Chalcones / Q000494:pharmacology* / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006035:Glycyrrhiza; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D047188:Chalcones; D004791:Enzyme Inhibitors; D010936:Plant Extracts; C040920:isoliquiritigenin; D042926:Cytochrome P-450 CYP4A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Anoikis; Breast cancer; COX-2; CYP 4A; Isoliquiritigenin; Metastasis