Antimetastatic effect and mechanism of ovatodiolide in MDA-MB-231 human breast cancer cells.
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.
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Taiwan.
Kuei-Li
KL
Lin
Pei-Chien
PC
Tsai
Chi-Ying
CY
Hsieh
Long-Sen
LS
Chang
Shinne-Ren
SR
Lin
D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D017931:DNA Primers; D004224:Diterpenes / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D004224:Diterpenes; D016328:NF-kappa B; C432447:ovatodiolide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt