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Article Publish Status: FREE
Abstract Title:

Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin.

Abstract Source:

Mol Ther Oncolytics. 2021 Mar 26 ;20:277-289. Epub 2021 Jan 20. PMID: 33614911

Abstract Author(s):

Guang-Yu Lian, Qing-Ming Wang, Thomas Shiu-Kwong Mak, Xiao-Ru Huang, Xue-Qing Yu, Hui-Yao Lan

Article Affiliation:

Guang-Yu Lian

Abstract:

Transforming growth factorβ (TGF-β) has been shown to promote tumor invasion and metastasis by activating the matrix metalloproteinases (MMPs); however, signaling mechanisms remain controversial and therapies targeting MMPs are still suboptimal. In the present study, we found that combined therapy with Asiatic acid (AA), aSmad7 agonist, and Naringenin (NG), a Smad3 inhibitor, effectively retrieved the balance between Smad3 and Smad7 signaling in the TGF-β-rich tumor microenvironment and thus significantly suppressed tumor invasion and metastasis in mouse models of melanoma and lung carcinoma. Mechanistically, we unraveled that Smad3 acted as a transcriptional activator of MMP2 and as a transcriptional suppressor of tissue inhibitors of metalloproteinase-2 (TIMP2) via binding to 5' UTR of MMP2 and 3' UTR of TIMP2, respectively. Treatment with NG inhibited Smad3-mediated MMP2 transcription while increasing TIMP, whereas treatment with AA enhanced Smad7 to suppress TGF-β/Smad3 signaling, as well as the activation of MMP2 by targeting the nuclear factor-κB (NF-κB)-membrane-type-1 MMP (MT1-MMP) axis. Therefore, the combination of AA and NG additively suppressed invasion and metastasis of melanoma and lungcarcinoma by targeting TGF-β/Smad-dependent MMP2 transcription, post-translational activation, and function.

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