Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway

Lee,Dae Hyung; Lim,In-Hye; Sung,Eon-Gi; Kim,Joo-Young; Song,In-Hwan; Park,Yoon Ki; Lee,Tae-Jin

doi:10.3892/or.2013.2487

Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway

Authors:
- Dae Hyung Lee
- In-Hye Lim
- Eon-Gi Sung
- Joo-Young Kim
- In-Hwan Song
- Yoon Ki Park
- Tae-Jin Lee
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Affiliations: Department of Obstetrics and Gynecology, Yeungnam University, Daegu 705-717, Republic of Korea, Department of Anatomy, College of Medicine, Yeungnam University, Daegu 705-717, Republic of Korea
Published online on: May 23, 2013 https://doi.org/10.3892/or.2013.2487
Pages: 933-938

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Abstract

Withaferin A (Wit A), a steroidal lactone isolated from Withania somnifera, exhibits anti-inflammatory, immunomodulatory 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.

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