title: Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway.
abstract: Withaferin A (Wit A), a steroidal lactone isolated from Withania somnifera, exhibits anti-inflammatory, immuno-modulatory and anti-angiogenic properties and antitumor activities. In the present study, we investigated the effects of Wit A on protease-mediated invasiveness of the human metastatic cancer cell lines Caski and SK-Hep1. We found that treatment with Wit A resulted in marked inhibition of the TGF‑β‑induced increase in expression and activity of matrix metalloproteinase (MMP)‑9 in Caski cell line. These effects of Wit A were dose-dependent and showed a correlation with suppression of MMP‑9 mRNA expression levels. Treatment with Wit A resulted in an ~1.6-fold induction of MMP-9 promoter activity, which was also suppressed by treatment with Wit A in Caski cells. We found that treatment with Wit A resulted in inhibition of TGF‑β‑induced phosphorylation of Akt, which was involved in the downregulation of expression of MMP-9 at the protein level. Introduction with constitutively active (CA)‑Akt resulted in a partial increase in the secretion of TGF-β-induced MMP-9 blocked by treatment with Wit A in Caski cells. According to these results, Wit A may inhibit the invasive and migratory abilities of Caski cells through a reduction in MMP-9 expression through suppression of the pAkt signaling pathway. These findings indicate that use of Wit A may be an effective strategy for control of metastasis and invasiveness of tumors.
authors.affiliation: Department of Obstetrics and Gynecology, Yeungnam University, Daegu 705-717, Republic of Korea.
authors.forename: Dae Hyung
authors.initials: DH
authors.lastname: Lee
authors.forename: In-Hye
authors.initials: IH
authors.lastname: Lim
authors.forename: Eon-Gi
authors.initials: EG
authors.lastname: Sung
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: In-Hwan
authors.initials: IH
authors.lastname: Song
authors.forename: Yoon Ki
authors.initials: YK
authors.lastname: Park
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Lee
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D016212:Transforming Growth Factor beta; D054358:Withanolides; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; C009684:withaferin A