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Andrographolide down-regulates hypoxia-inducible factor-1{alpha} in human non-small cell lung cancer A549 cells

Abstract

Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to inhibit non-small cell lung cancer (NSCLC) A549 cell migration and invasion via down-regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Here we demonstrated that Andro inhibited the expression of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) in A549 cells. HIF-1{alpha} plays an important role in tumor growth, angiogenesis and lymph node metastasis of NSCLC. The Andro-induced decrease of cellular protein level of HIF-1{alpha} was correlated with a rapid ubiquitin-dependent degradation of HIF-1{alpha}, and was accompanied by increased expressions of hydroxyl-HIF-1{alpha} and prolyl hydroxylase (PHD2), and a later decrease of vascular endothelial growth factor (VEGF) upon the treatment of Andro. The Andro-inhibited VEGF expression appeared to be a consequence of HIF-1{alpha} inactivation, because its DNA binding activity was suppressed by Andro. Molecular data showed that all these effects of Andro might be mediated via TGF{beta}1/PHD2/HIF-1{alpha} pathway, as demonstrated by the transfection of TGF{beta}1 overexpression vector and PHD2 siRNA, and the usage of a pharmacological MG132 inhibitor. Furthermore, we elucidated the involvement of Andro in HIF-1{alpha} transduced VEGF expression in A549 cells and other NSCLC cell lines. In  More>>
Authors:
Lin, Hui-Hsuan; [1]  Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China)]; Tsai, Chia-Wen; [2]  Chou, Fen-Pi; [3]  Wang, Chau-Jong; [4]  Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China)]; Hsuan, Shu-Wen; [5]  Wang, Cheng-Kun; [6]  Chen, Jing-Hsien [5] 
  1. School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China)
  2. Department of Nutrition, China Medical University, Taichung, Taiwan (China)
  3. Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China)
  4. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China)
  5. Department of Medical Laboratory Science and Biotechnology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, No.89, Wen Hwa 1st St., Rende Shiang, Tainan County 717, Taiwan (China)
  6. E-Chyun Dermatology Clinic, No.70, Sec. 3, Jhonghua E. Rd., East District, Tainan, Taiwan (China)
Publication Date:
Feb 01, 2011
Product Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 250; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2010.11.014; PII: S0041-008X(10)00446-1; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.
Subject:
60 APPLIED LIFE SCIENCES; ANGIOGENESIS; CHEMILUMINESCENCE; DNA; ELECTROPHORESIS; GROWTH FACTORS; HUMAN POPULATIONS; LUNGS; LYMPH NODES; NEOPLASMS; BODY; DISEASES; EMISSION; LUMINESCENCE; LYMPHATIC SYSTEM; MITOGENS; NUCLEIC ACIDS; ORGANIC COMPOUNDS; ORGANS; PHOTON EMISSION; POPULATIONS; PROTEINS; RESPIRATORY SYSTEM
OSTI ID:
21535231
Country of Origin:
United States
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 0041-008X; TXAPA9; TRN: US11R1413014180
Availability:
Available from http://dx.doi.org/10.1016/j.taap.2010.11.014
Submitting Site:
INIS
Size:
page(s) 336-345
Announcement Date:
Mar 17, 2012

Citation Formats

Lin, Hui-Hsuan, Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China)], Tsai, Chia-Wen, Chou, Fen-Pi, Wang, Chau-Jong, Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China)], Hsuan, Shu-Wen, Wang, Cheng-Kun, and Chen, Jing-Hsien. Andrographolide down-regulates hypoxia-inducible factor-1{alpha} in human non-small cell lung cancer A549 cells. United States: N. p., 2011. Web. doi:10.1016/j.taap.2010.11.014.
Lin, Hui-Hsuan, Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China)], Tsai, Chia-Wen, Chou, Fen-Pi, Wang, Chau-Jong, Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China)], Hsuan, Shu-Wen, Wang, Cheng-Kun, & Chen, Jing-Hsien. Andrographolide down-regulates hypoxia-inducible factor-1{alpha} in human non-small cell lung cancer A549 cells. United States. doi:10.1016/j.taap.2010.11.014.
Lin, Hui-Hsuan, Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China)], Tsai, Chia-Wen, Chou, Fen-Pi, Wang, Chau-Jong, Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China)], Hsuan, Shu-Wen, Wang, Cheng-Kun, and Chen, Jing-Hsien. 2011. "Andrographolide down-regulates hypoxia-inducible factor-1{alpha} in human non-small cell lung cancer A549 cells." United States. doi:10.1016/j.taap.2010.11.014. https://www.osti.gov/servlets/purl/10.1016/j.taap.2010.11.014.
@misc{etde_21535231,
title = {Andrographolide down-regulates hypoxia-inducible factor-1{alpha} in human non-small cell lung cancer A549 cells}
author = {Lin, Hui-Hsuan, Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan (China)], Tsai, Chia-Wen, Chou, Fen-Pi, Wang, Chau-Jong, Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China)], Hsuan, Shu-Wen, Wang, Cheng-Kun, and Chen, Jing-Hsien}
abstractNote = {Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess multiple pharmacological activities. In our previous study, Andro had been shown to inhibit non-small cell lung cancer (NSCLC) A549 cell migration and invasion via down-regulation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Here we demonstrated that Andro inhibited the expression of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) in A549 cells. HIF-1{alpha} plays an important role in tumor growth, angiogenesis and lymph node metastasis of NSCLC. The Andro-induced decrease of cellular protein level of HIF-1{alpha} was correlated with a rapid ubiquitin-dependent degradation of HIF-1{alpha}, and was accompanied by increased expressions of hydroxyl-HIF-1{alpha} and prolyl hydroxylase (PHD2), and a later decrease of vascular endothelial growth factor (VEGF) upon the treatment of Andro. The Andro-inhibited VEGF expression appeared to be a consequence of HIF-1{alpha} inactivation, because its DNA binding activity was suppressed by Andro. Molecular data showed that all these effects of Andro might be mediated via TGF{beta}1/PHD2/HIF-1{alpha} pathway, as demonstrated by the transfection of TGF{beta}1 overexpression vector and PHD2 siRNA, and the usage of a pharmacological MG132 inhibitor. Furthermore, we elucidated the involvement of Andro in HIF-1{alpha} transduced VEGF expression in A549 cells and other NSCLC cell lines. In conclusion, these results highlighted the potential effects of Andro, which may be developed as a chemotherapeutic or an anti-angiogenesis agent for NSCLC in the future.}
doi = {10.1016/j.taap.2010.11.014}
journal = {Toxicology and Applied Pharmacology}
issue = {3}
volume = {250}
place = {United States}
year = {2011}
month = {Feb}
}