Abstract
Salinomycin (Sal) is a recently identified anti-tumor drug for treating several types of solid tumor; however, its effects on the migratory and invasive properties of non-small cell lung cancer (NSCLC) remain unclear. This study investigated the inhibitory effect underlying mechanisms of Salon transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) and cell migration. Sal solidly blocked cell migration and invasion enhancement by TGF-β1-induced EMT, through recovering E-cadherin loss and suppressing mesenchymal markers induction, as well as TGF-β1-mediated AMPK/SIRT signaling activity upregulation. The pharmacologic inhibition or knockdown of AMPK or SIRT1 can act synergistically with Sal to inhibit TGF-β1-induced MMP-2 and MMP-9. In contrast, AMPK or SIRT1 upregulation can protect against TGF-β1-induced MMP-2 and MMP-9 inhibition by Sal. Next we demonstrated that the MMP-2 and MMP-9 knockdown can act synergistically with Sal to inhibit TGF-β1-induced EMT. Moreover, treatment of PMA of MMP activator increased TGF-β1-induced MMP-2 and MMP-9, even with Sal. Our results demonstrate that Sal suppresses TGF-β1-induced EMT by downregulating MMP-2 and MMP-9 through the AMPK/SIRT pathway, thereby inhibiting lung cancer cell migration and invasion.
Keywords:
AMPK; EMT; Lung cancer; MMP; SIRT; Salinomycin; TGF-β1.
© The author(s).
MeSH terms
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / genetics
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Down-Regulation / drug effects
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Epithelial-Mesenchymal Transition / drug effects
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Epithelial-Mesenchymal Transition / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Knockdown Techniques
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / prevention & control
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Pyrans / pharmacology*
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Pyrans / therapeutic use
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sirtuin 1 / antagonists & inhibitors
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Sirtuin 1 / genetics
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Sirtuin 1 / metabolism
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Transforming Growth Factor beta1 / antagonists & inhibitors
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Transforming Growth Factor beta1 / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Pyrans
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TGFB1 protein, human
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Transforming Growth Factor beta1
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salinomycin
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AMP-Activated Protein Kinases
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MMP2 protein, human
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Matrix Metalloproteinase 2
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MMP9 protein, human
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Matrix Metalloproteinase 9
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SIRT1 protein, human
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Sirtuin 1