Adenosine dialdehyde suppresses MMP-9-mediated invasion of cancer cells by blocking the Ras/Raf-1/ERK/AP-1 signaling pathway.

Abstract

Adenosine dialdehyde (AdOx) inhibits transmethylation by the accumulation of S-adenosylhomocysteine (SAH), a negative feedback inhibitor of methylation, through the suppression of SAH hydrolase (SAHH). In this study, we aimed to determine the regulatory effect of AdOx on cancer invasion by using three different cell lines: MDA-MB-231, MCF-7, and U87. The invasive capacity of these cells in the presence (MCF-7) or absence (MDA-MB-231 and U87) of phorbal 12-myristate 13-acetate (PMA) was strongly decreased by AdOx treatment. Furthermore, the expression, secretion, and activation of matrix metalloproteinase (MMP)-9, a critical enzyme regulating cell invasion, in these cells were diminished by AdOx treatment. AdOx strongly suppressed AP-1-mediated luciferase activity and, in parallel, reduced the translocation of c-Fos and c-Jun into the nucleus. AdOx was shown to block a series of upstream AP-1 activation signaling complexes composed of extracellular signal-related kinase (ERK), mitogen-activated protein ERK kinase (MEK)1/2, Raf-1, and Ras, as assessed by measuring the levels of the phosphorylated and membrane-translocated forms. Furthermore, we found that suppression of SAHH by siRNA and 3-deazaadenosine, knock down of isoprenylcysteine carboxyl methyltransferase (ICMT), and treatment with SAH showed inhibitory patterns similar to those of AdOx. Therefore, our data suggest that AdOx is capable of targeting the methylation reaction regulated by SAHH and ICMT and subsequently downregulating MMP-9 expression and decreasing invasion of cancer cells through inhibition of the Ras/Raf-1/ERK/AP-1 pathway.

• Authors: Ji Hye Kim, Jong Heon Kim, Seung Cheol Kim, Young-Su Yi, Woo Seok Yang, Yanyan Yang, Han Gyung Kim, Jae Yong Lee, Kyung-Hee Kim, Byong Chul Yoo, Sungyoul Hong, Jae Youl Cho
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 86 Issue 9 Pg. 1285-300 (Nov 01 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23994169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• RNA, Small Interfering
• Transcription Factor AP-1
• 3-deazaadenosine
• periodate-oxidized adenosine
• Protein Methyltransferases
• protein-S-isoprenylcysteine O-methyltransferase
• Proto-Oncogene Proteins c-raf
• Matrix Metalloproteinase 9
• ras Proteins
• ACSM3 protein, human
• Coenzyme A Ligases
• Adenosine
• Tubercidin

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor (drug effects, pathology)
• Cell Movement (drug effects)
• Coenzyme A Ligases (genetics, metabolism)
• Humans
• MAP Kinase Signaling System (drug effects)
• MCF-7 Cells (drug effects)
• Matrix Metalloproteinase 9 (metabolism)
• Methylation (drug effects)
• Phosphorylation (drug effects)
• Protein Methyltransferases (metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• RNA, Small Interfering
• Signal Transduction (drug effects)
• Transcription Factor AP-1 (metabolism)
• Tubercidin (pharmacology)
• ras Proteins (metabolism)