Antimetastatic effect and mechanism of ovatodiolide in MDA-MB-231 human breast cancer cells.

Abstract

Cancer metastasis is a primary cause of cancer death. Ovatodiolide, a bioactive cembrane-type diterpenoid isolated from Anisomeles indica (L.) Kuntze (Labiatae), has been shown to inhibit the growth and proliferation of cancer cells. However, the anti-metastatic effects of ovatodiolide on highly metastatic human breast cancer MDA-MB-231 cells remain unclear. In this study, we first noted that ovatodiolide inhibited MDA-MB-231 cell migration and invasion by wound-healing assay and Boyden chamber assay. Western blot, gelatin zymography and reversed transcription-PCR analysis showed that ovatodiolide significantly and selectively suppressed the expression, activation, and mRNA of matrix metalloproteinase-9 (MMP-9) in a concentration-dependent manner. Ovatodiolide significantly decreased the nuclear level of nuclear factor kappaB (NF-κB), increased inhibitor of kappaBα (IκBα) through preventing phosphorylation of upstream signal IκB kinase (IKK). Pretreatment with a specific NF-κB inhibitor (PDTC) and an IκB protease inhibitor (TPCK) also reduced MMP-9 activity, cell migration and cell invasion. Moreover, ovatodiolide can suppress activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase and Akt, while it did not affect phosphorylation of extracellular signal regulating kinases (ERK)1/2. Additionally, the treatment of inhibitors specific for PI3K (wortmannin), JNK (SP600125) or p38 MAPK (SB203580) to MDA-MB-231 cells could result in a reduced activation of MMP-9, concomitantly with a marked inhibition on cell migration and invasion. Taken together, these results demonstrate that ovatodiolide inhibits the metastatic ability of MDA-MB-231 cells by reducing MMP-9 activity through suppressing JNK, p38 MAPK and PI3K/Akt signaling pathways and inhibiting NF-κB activity. These results are the first to reveal the function of ovatodiolide in tumor metastasis and its underlying molecular mechanism, thus suggesting ovatodiolide to be a promising antimetastatic agent.

• Authors: Kuei-Li Lin, Pei-Chien Tsai, Chi-Ying Hsieh, Long-Sen Chang, Shinne-Ren Lin
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 194 Issue 2-3 Pg. 148-58 (Nov 15 2011) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 22033475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• DNA Primers
• Diterpenes
• NF-kappa B
• ovatodiolide
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Base Sequence
• Blotting, Western
• Breast Neoplasms (metabolism, pathology)
• Cell Cycle
• Cell Line, Tumor
• DNA Primers
• Diterpenes (therapeutic use)
• Female
• Humans
• MAP Kinase Signaling System
• NF-kappa B (metabolism)
• Neoplasm Metastasis (drug therapy)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction