ReferenceID 4582
Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin
Mol Ther Oncolytics
Transforming growth factor beta (TGF-beta) has been shown to promote tumor invasion and metastasis by activating the matrix metalloproteinases (MMPs); however, signaling mechanisms remain controversial and therapies targ
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Record Fields
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- Reference Id
- 4582
- Evidence Id
- 21172
- Core Evidence Id
- 21172
- Source Reference Id
- 2429
- Herb2 Reference Id
- HBREF003226
- Subject Paper Key
- HBIN017057_33614911
- Pubmed Id
- 33614911
- Doi
- 10.1016/j.omto.2021.01.006
- Paper Title
- Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin
- Paper Abstract
- Transforming growth factor beta (TGF-beta) 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), a Smad7 agonist, and Naringenin (NG), a Smad3 inhibitor, effectively retrieved the balance between Smad3 and Smad7 signaling in the TGF-beta-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-beta/Smad3 signaling, as well as the activation of MMP2 by targeting the nuclear factor-kappaB (NF-kappaB)-membrane-type-1 MMP (MT1-MMP) axis. Therefore, the combination of AA and NG additively suppressed invasion and metastasis of melanoma and lung carcinoma by targeting TGF-beta/Smad-dependent MMP2 transcription, post-translational activation, and function.
- Journal
- Mol Ther Oncolytics
- Publish Year
- 2021
- Experiment Subject
- mouse
- Experiment Type
- Animal Experiment
- Phenotype Related
- Melanoma; Tumor; Lung Carcinoma
- Paper Title Cn
- Paper Title En
- Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin
- Bilingual Status
- semi_complete