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 (Tyr458), phospho-PDK (Ser241) and phospho-Akt (Thr308). 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 (Thr308). 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.
- Publication:
-
Toxicology and Applied Pharmacology
- Pub Date:
- October 2014
- DOI:
- 10.1016/j.taap.2014.07.018
- Bibcode:
- 2014ToxAP.280...10Z
- Keywords:
-
- ISL;
- isoliquiritigenin;
- AA;
- arachidonic acid;
- COX;
- cyclooxygenase;
- LOX;
- lipoxygenase;
- CYP;
- cytochrome P450;
- PGE<SUB loc="post">2</SUB>;
- prostaglandin E<SUB loc="post">2</SUB>;
- LTB<SUB loc="post">4</SUB>;
- leukotriene B4;
- 20-HETE;
- 20-hydroxyeicosatetraenoic acid;
- EP;
- prostaglandin receptor;
- FLAP;
- 5-lipoxygenase activating protein;
- BLT;
- leukotriene B4 receptor;
- PI3K;
- Phosphatidylinositol 3-kinase;
- HPLC;
- high-performance liquid chromatography;
- ELISA;
- enzyme-linked immunosorbent assay;
- DMSO;
- dimethyl sulfoxide;
- poly-HEMA;
- polyhydroxyethyl methacrylate;
- PI;
- propidium iodide;
- MMP;
- matrix metallopeptidase;
- FBS;
- fetal bovine serum;
- RPMI;
- Roswell Park Memorial Institute;
- GSK;
- phospho-glycogen synthase kinase;
- LC-ESI-MS/MS;
- liquid chromatographic-electrospray ionization-tandem mass spectrometry;
- HNSCC;
- head and neck squamous cell carcinoma;
- sPLA2;
- secretory phospholipase A2;
- qPCR;
- quantitative real-time polymerase chain reaction;
- CV;
- coefficient of variation;
- Anoikis;
- Breast cancer;
- COX-2;
- CYP 4A;
- Isoliquiritigenin;
- Metastasis