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Chem Biol Interact. 2017 Aug 1;273:228-236. doi: 10.1016/j.cbi.2017.06.024. Epub 2017 Jun 23.

Andrographolide reduced VEGFA expression in hepatoma cancer cells by inactivating HIF-1α: The involvement of JNK and MTA1/HDCA.

Author information

1
Shanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2
Shanghai Children's Medical Center, Shanghai 200127, China.
3
Shanghai Key Laboratory of Complex Prescription, The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: lichenyue1307@126.com.

Abstract

Andrographolide (Andro) is the main active compound in medicinal herb Andrographis paniculata Nees (Acanthaceae). Vascular endothelial growth factor A (VEGFA), a key pro-angiogenic factor, contributes greatly to tumor growth. The purpose of this study is to observe the inhibition of Andro on VEGFA expression in hepatoma cancer cells and its engaged mechanism. Andro decreased mRNA and protein expression of VEGFA in hepatoma Hep3B and HepG2 cells. Andro also decreased hypoxia-inducible factor 1-alpha (HIF-1α) protein expression and its subsequent nuclear translocation. Further results showed that Andro induced the polyubiquitination of HIF-1α protein, and proteasome inhibitor MG132 reversed Andro-induced decrease in the expression of HIF-1α protein and VEGFA mRNA and protein. Andro reduced the expression of metastasis-associated protein 1 (MTA1) and histone deacetylase 1 (HDAC1) in hepatoma cancer cells. SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), reversed Andro-induced decrease in the expression of HIF-1α and VEGFA, but not MTA1 and HDAC1. Andro (10 mg/kg) inhibited tumor growth in mice implanted with hepatoma Hep3B cells in vivo, and reduced the expression of CD31, VEGFA and HIF-1α in tumor tissues. In conclusion, Andro inhibited hepatoma tumor growth by reducing HIF-1α expression and its-mediated VEGFA expression via inducing ubiquitination-mediated HIF-1α protein degradation, and JNK and MTA1/HDAC1 may be involved in this process. Natural product Andro has huge potential in hepatoma cancer treatment.

KEYWORDS:

Andrographolide; HIF-1α; Hepatoma cancer; JNK; MTA1; VEGFA

PMID:
28651835
DOI:
10.1016/j.cbi.2017.06.024
[Indexed for MEDLINE]

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