Journal
INTERNATIONAL JOURNAL OF MEDICAL SCIENCES
Volume 18, Issue 3, Pages 715-726Publisher
IVYSPRING INT PUBL
DOI: 10.7150/ijms.50080
Keywords
Salinomycin; TGF-beta 1; EMT; AMPK; SIRT; MMP; Lung cancer
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Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2018R1D1A1B07050757, 2015R1D1A1 A01057580]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI15C1951]
- National Research Foundation of Korea [2018R1D1A1B07050757] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Salinomycin (Sal) inhibits TGF-beta 1-induced EMT by downregulating MMP-2 and MMP-9 through the AMPK/SIRT pathway, thereby blocking lung cancer cell migration and invasion.
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-beta 1 (TGF-beta 1)-induced epithelial-to-mesenchymal transition (EMT) and cell migration. Sal solidly blocked cell migration and invasion enhancement by TGF-beta 1-induced EMT, through recovering E-cadherin loss and suppressing mesenchymal markers induction, as well as TGF-beta 1-mediated AMPK/SIRT signaling activity upregulation. The pharmacologic inhibition or knockdown of AMPK or SIRT1 can act synergistically with Sal to inhibit TGF-beta 1-induced MMP-2 and MMP-9. In contrast, AMPK or SIRT1 upregulation can protect against TGF-beta 1-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-beta 1-induced EMT. Moreover, treatment of PMA of MMP activator increased TGF-beta 1-induced MMP-2 and MMP-9, even with Sal. Our results demonstrate that Sal suppresses TGF-beta 1-induced EMT by downregulating MMP-2 and MMP-9 through the AMPK/SIRT pathway, thereby inhibiting lung cancer cell migration and invasion.
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