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

ABSTRACT: Transforming growth factor ? (TGF-?) 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-?-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-?/Smad3 signaling, as well as the activation of MMP2 by targeting the nuclear factor-?B (NF-?B)-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-?/Smad-dependent MMP2 transcription, post-translational activation, and function.

SUBMITTER: Lian GY

PROVIDER: S-EPMC7873580 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Lian Guang-Yu GY Wang Qing-Ming QM Mak Thomas Shiu-Kwong TS Huang Xiao-Ru XR Yu Xue-Qing XQ Lan Hui-Yao HY

Molecular therapy oncolytics 20210120

Transforming growth factor β (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), a Smad7 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 s ...[more]

PMID: 33614911

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Project description:BackgroundGlioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood.MethodsU251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.ResultsHere we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better "turn off" tumor growth.ConclusionOur findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells' invasion.

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

Publications

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

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