Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer.

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.

• Authors: Ying Li, Haixia Zhao, Yuzhong Wang, Hao Zheng, Wei Yu, Hongyan Chai, Jing Zhang, John R Falck, Austin M Guo, Jiang Yue, Renxiu Peng, Jing Yang
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 272 Issue 1 Pg. 37-48 (Oct 01 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 23747687 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Chalcones
• Eicosanoids
• Enzyme Inhibitors
• Indicators and Reagents
• Phosphoinositide-3 Kinase Inhibitors
• Arachidonic Acid
• isoliquiritigenin
• Oncogene Protein v-akt
• Caspases

Topics

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