title: 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.affiliation: Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhao
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Hongyan
authors.initials: H
authors.lastname: Chai
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Austin M
authors.initials: AM
authors.lastname: Guo
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
authors.forename: Renxiu
authors.initials: R
authors.lastname: Peng
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D006035:Glycyrrhiza / Q000737:chemistry; D006801:Humans; D007202:Indicators and Reagents; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018517:Plant Roots / Q000737:chemistry; D014162:Transfection; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047188:Chalcones; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016718:Arachidonic Acid; C040920:isoliquiritigenin; D051058:Oncogene Protein v-akt; D020169:Caspases
keywords: Akt; Apoptosis; Breast cancer; Eicosanoids; Isoliquiritigenin; PI3k