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

作者：Lin Hui Hsuan; Tsai Chia Wen; Chou Fen Pi; Wang Chau Jong; Hsuan Shu Wen; Wang Cheng Kun; Chen Jing Hsien^*

来源：Toxicology and Applied Pharmacology, 2011, 250(3): 336-345.

DOI：10.1016/j.taap.2010.11.014

• Andrographolide
• Non-small cell lung cancer A549 cell
• Hypoxia-inducible factor-1 alpha
• Prolyl hydroxylase
• Vascular endothelial growth factor

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.

• 出版日期2011-2-1
• 单位中国医科大学