NYMC Faculty Publications

Isoliquiritigenin Induces Growth Inhibition and Apoptosis Through Downregulating Arachidonic Acid Metabolic Network and the Deactivation of PI3K/Akt in Human Breast Cancer

Author Type(s)

Faculty

DOI

10.1016/j.taap.2013.05.031

Journal Title

Toxicology and Applied Pharmacology

First Page

37

Last Page

48

Document Type

Article

Publication Date

10-1-2013

Department

Pharmacology

Keywords

Animals, Antineoplastic Agents, Phytogenic, Apoptosis, Arachidonic Acid, Blotting, Western, Breast Neoplasms, Caspases, Cell Line, Tumor, Cell Proliferation, Chalcones, Down-Regulation, Eicosanoids, Enzyme Inhibitors, Female, Gene Expression Profiling, Glycyrrhiza, Humans, Indicators and Reagents, Mice, Mice, Inbred BALB C, Mice, Nude, Oncogene Protein v-akt, Phosphoinositide-3 Kinase Inhibitors, Plant Roots, Transfection, Tumor Stem Cell Assay, Xenograft Model Antitumor Assays

Disciplines

Medicine and Health Sciences

Abstract

Arachidonic acid (AA)-derived eicosanoids and its downstream pathways have been demonstrated to play crucial roles in growth control of breast cancer. Here, we demonstrate that isoliquiritigenin, a flavonoid phytoestrogen from licorice, induces growth inhibition and apoptosis through downregulating multiple key enzymes in AA metabolic network and the deactivation of PI3K/Akt in human breast cancer. Isoliquiritigenin diminished cell viability, 5-bromo-2'-deoxyuridine (BrdU) incorporation, and clonogenic ability in both MCF-7 and MDA-MB-231cells, and induced apoptosis as evidenced by an analysis of cytoplasmic histone-associated DNA fragmentation, flow cytometry and hoechst staining. Furthermore, isoliquiritigenin inhibited mRNA expression of multiple forms of AA-metabolizing enzymes, including phospholipase A2 (PLA2), cyclooxygenases (COX)-2 and cytochrome P450 (CYP) 4A, and decreased secretion of their products, including prostaglandin E2 (PGE2) and 20-hydroxyeicosatetraenoic acid (20-HETE), without affecting COX-1, 5-lipoxygenase (5-LOX), 5-lipoxygenase activating protein (FLAP), and leukotriene B4 (LTB4). In addition, it downregulated the levels of phospho-PI3K, phospho-PDK (Ser(241)), phospho-Akt (Thr(308)), phospho-Bad (Ser(136)), and Bcl-xL expression, thereby activating caspase cascades and eventually cleaving poly(ADP-ribose) polymerase (PARP). Conversely, the addition of exogenous eicosanoids, including PGE2, LTB4 and a 20-HETE analog (WIT003), and caspase inhibitors, or overexpression of constitutively active Akt reversed isoliquiritigenin-induced apoptosis. Notably, isoliquiritigenin induced growth inhibition and apoptosis of MDA-MB-231 human breast cancer xenografts in nude mice, together with decreased intratumoral levels of eicosanoids and phospho-Akt (Thr(308)). Collectively, these data suggest that isoliquiritigenin induces growth inhibition and apoptosis through downregulating AA metabolic network and the deactivation of PI3K/Akt in human breast cancer.

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