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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 E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE), without affecting COX-1, 5-lipoxygenase (5-LOX), 5-lipoxygenase activating protein (FLAP), and leukotriene B{sub 4} (LTB{sub 4}). In addition, it downregulated the levels of phospho-PI3K, phospho-PDK (Ser{sup 241}), phospho-Akt (Thr{sup 308}), phospho-Bad (Ser{sup 136}), and Bcl-x{sub L} expression, thereby activating caspase cascades and eventually cleaving poly(ADP-ribose) polymerase (PARP). Conversely, the addition of exogenous eicosanoids, including PGE{sub 2}, LTB{sub 4} and a 20-HETE analog (WIT003), and caspase inhibitors, or overexpression of constitutively active Akt reversed isoliquiritigenin-induced apoptosis. Notably,more » 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{sup 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. - Highlights: • Isoliquiritigenin induces growth inhibition and apoptosis in human breast cancer. • The proapoptotic action of isoliquiritigenin has been studied in vitro and in vivo. • Arachidonic acid metabolic network mediates isoliquiritigenin-induced apoptosis. • PI3K/Akt deactivation is asssociated with isoliquiritigenin-induced apoptosis. • Isoliquiritigenin may be a multi-target drug in the treatment of breast cancer.« less

Authors:
;  [1];  [2]; ; ;  [1];  [3];  [4];  [1]; ;  [1];  [1]
  1. Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)
  2. Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079 (China)
  3. Animal Experimental Center of Wuhan University, Wuhan 430071 (China)
  4. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390,USA (United States)
Publication Date:
OSTI Identifier:
22285393
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 272; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADP; APOPTOSIS; ARACHIDONIC ACID; DEOXYURIDINE; DNA; ENZYMES; IN VITRO; MAMMARY GLANDS; MESSENGER-RNA; MICE; NEOPLASMS; PROSTAGLANDINS; RIBOSE

Citation Formats

Li, Ying, Zhao, Haixia, Wang, Yuzhong, Zheng, Hao, Yu, Wei, Chai, Hongyan, Zhang, Jing, Falck, John R., Guo, Austin M., Department of Pharmacology, New York Medical College, Valhalla, NY 10595, Yue, Jiang, Peng, Renxiu, Yang, Jing, and Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071. Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.05.031.
Li, Ying, Zhao, Haixia, Wang, Yuzhong, Zheng, Hao, Yu, Wei, Chai, Hongyan, Zhang, Jing, Falck, John R., Guo, Austin M., Department of Pharmacology, New York Medical College, Valhalla, NY 10595, Yue, Jiang, Peng, Renxiu, Yang, Jing, & Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071. Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer. United States. https://doi.org/10.1016/J.TAAP.2013.05.031
Li, Ying, Zhao, Haixia, Wang, Yuzhong, Zheng, Hao, Yu, Wei, Chai, Hongyan, Zhang, Jing, Falck, John R., Guo, Austin M., Department of Pharmacology, New York Medical College, Valhalla, NY 10595, Yue, Jiang, Peng, Renxiu, Yang, Jing, and Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071. 2013. "Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer". United States. https://doi.org/10.1016/J.TAAP.2013.05.031.
@article{osti_22285393,
title = {Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer},
author = {Li, Ying and Zhao, Haixia and Wang, Yuzhong and Zheng, Hao and Yu, Wei and Chai, Hongyan and Zhang, Jing and Falck, John R. and Guo, Austin M. and Department of Pharmacology, New York Medical College, Valhalla, NY 10595 and Yue, Jiang and Peng, Renxiu and Yang, Jing and Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071},
abstractNote = {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 E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE), without affecting COX-1, 5-lipoxygenase (5-LOX), 5-lipoxygenase activating protein (FLAP), and leukotriene B{sub 4} (LTB{sub 4}). In addition, it downregulated the levels of phospho-PI3K, phospho-PDK (Ser{sup 241}), phospho-Akt (Thr{sup 308}), phospho-Bad (Ser{sup 136}), and Bcl-x{sub L} expression, thereby activating caspase cascades and eventually cleaving poly(ADP-ribose) polymerase (PARP). Conversely, the addition of exogenous eicosanoids, including PGE{sub 2}, LTB{sub 4} 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{sup 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. - Highlights: • Isoliquiritigenin induces growth inhibition and apoptosis in human breast cancer. • The proapoptotic action of isoliquiritigenin has been studied in vitro and in vivo. • Arachidonic acid metabolic network mediates isoliquiritigenin-induced apoptosis. • PI3K/Akt deactivation is asssociated with isoliquiritigenin-induced apoptosis. • Isoliquiritigenin may be a multi-target drug in the treatment of breast cancer.},
doi = {10.1016/J.TAAP.2013.05.031},
url = {https://www.osti.gov/biblio/22285393}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 272,
place = {United States},
year = {Tue Oct 01 00:00:00 EDT 2013},
month = {Tue Oct 01 00:00:00 EDT 2013}
}