Andrographolide down-regulates hypoxia-inducible factor-1α in human non-small cell lun g cancer A549 cells

Toxicol Appl Pharmacol. 2010 Dec 3. [Epub ahead of print]

Andrographolide down-regulates hypoxia-inducible factor-1α in human non-small cell lun g cancer A549 cells.

Lin HH, Tsai CW, Chou FP, Wang CJ, Hsuan SW, Wang CK, Chen JH.

School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.

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-1α (HIF-1α) in A549 cells. HIF-1α plays an important role in tumor growth, angiogenesis and lymph node metastasis of NSCLC. The Andro-induced decrease of cellular protein level of HIF-1α was correlated with a rapid ubiquitin-dependent degradation of HIF-1α, and was accompanied by increased expressions of hydroxyl-HIF-1α 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-1α inactivation, because that its DNA binding activity was suppressed by Andro. Molecular data showed that all these effects of Andro might be mediated via TGFβ1/PHD2/HIF-1α pathway, as demonstrated by the transfection of TGFβ1 overexpression vector and PHD2 siRNA, and the usage of a pharmacological MG132 inhibitor. Furthermore, we elucidated the involvement of Andro in HIF-1α 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 chemotheraptic or an anti-angiogenesis agent for NSCLC in the future.

Copyright © 2010. Published by Elsevier Inc.
PMID: 21134392 [PubMed - as supplied by publisher]