Abstract
Abstract Andrographolide is the major chemical component of an herbal plant, Andrographis paniculata, and has been reported to exhibit anti-cancer activity. We had previously demonstrated that andrographolide can suppress the migration and invasion of a highly metastatic melanoma cell, B16F10, but the molecular target and regulatory mechanism underlying this phenomenon remain unknown. A chemical proteomics approach using serine hydrolase activity probes and mass spectrometry-based identification was carried out to reveal that monoacylglycerol lipase (MAGL) of lipid metabolism is involved in the andrographolide-mediated suppression of B16F10 cell migration. MAGL has been reported to be elevated in aggressive cancers and associated with tumor metastasis. We observed that the hydrolase activity of MAGL in B16F10 cells was decreased upon andrographolide treatment but not in the poorly metastatic B16F1 cells. In addition, a known MAGL-specific inhibitor (JZL184) was used to demonstrate that suppression of MAGL enzyme activity could reduce B16F10 migration. Notably, overexpression of MAGL in B16F10 cells abrogated the andrographolide-mediated suppression of B16F10 migration, but such overexpression could not rescue the JZL184-mediated suppression. Further analysis showed a downregulation of MAGL mRNA levels in B16F10 cells upon treatment of andrographolide. With the use of an IKK inhibitor (Bay11-7082), the NF-kB signaling pathway is shown to be involved in the andrographolide-mediated suppression of MAGL expression. Taken together, we herein demonstrate that andrographolide suppresses melanoma cell migration via transcriptional downregulation of monoacylglycerol lipase, providing a new anti-cancer mechanism of andrographolide and a basis for further development of potent derivatives. Citation Format: Ya-Hsin Hsu, Ting-Yun Huang, Lee-Chiang Lo, Shu-Ling Fu, Chao-Hsiung Lin. Chemical proteomics approach reveals a monoacylglycerol lipase-dependent migration suppression of melanoma cells by andrographolide. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-31.
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