Andrographolide suppresses the migratory ability of human glioblastoma multiforme cells by targeting ERK1/2-mediated matrix metalloproteinase-2 expression

// Shih-Liang Yang 1, 2, * , Fu-Hsuan Kuo 3, * , Pei-Ni Chen 4, 5 , Yi-Hsien Hsieh 4, 5 , Nuo-Yi Yu 1 , Wei-En Yang 1, 6 , Ming-Ju Hsieh 1, 7, 8 and Shun-Fa Yang 1, 6 1 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan 2 Department of Traditional Chinese Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan 3 Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan 4 Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan 5 Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan 6 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan 7 Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan 8 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Ming-Ju Hsieh, email: 170780@cch.org.tw Shun-Fa Yang, email: ysf@csmu.edu.tw Keywords: glioblastoma multiforme; andrographolide; migration; CREB Received: September 08, 2017 Accepted: September 23, 2017 Published: November 11, 2017 ABSTRACT Glioblastoma multiforme (GBM) can be a fatal tumor because of difficulties in treating the related metastasis. Andrographolide is the bioactive component of the Andrographis paniculata . Andrographolide possesses the anti-inflammatory activity and inhibits the growth of various cancers; however, its effect on GBM cancer motility remains largely unknown. In this study, we examined the antimetastatic properties of andrographolide in human GBM cells. Our results revealed that andrographolide inhibited the invasion and migration abilities of GBM8401 and U251 cells. Furthermore, andrographolide inhibited matrix metalloproteinase (MMP)-2 activity and expression. Real-time PCR and promoter activity assays indicated that andrographolide inhibited MMP-2 expression at the transcriptional level. Such inhibitory effects were associated with the suppression of CREB DNA-binding activity and CREB expression. Mechanistically, andrographolide inhibited the cell motility of GBM8401 cells through the extracellular-regulated kinase (ERK) 1/2 pathway, and the blocking of the ERK 1/2 pathway could reverse MMP-2-mediated cell motility. In conclusion, CREB is a crucial target of andrographolide for suppressing MMP-2-mediated cell motility in GBM cells. Therefore, a combination of andrographolide and an ERK inhibitor might be a good strategy for preventing GBM metastasis.