Salinomycin suppresses TGF-β1-induced EMT by down-regulating MMP-2 and MMP-9 via the AMPK/SIRT1 pathway in non-small cell lung cancer

Hwang, Ki-Eun; Kim, Hyo-Jin; Song, In-Sol; Park, Chul; Jung, Jae Wan; Park, Do-Sim; Oh, Seon-Hee; Kim, Young-Suk; Kim, Hak-Ryul

doi:10.7150/ijms.50080

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Int J Med Sci 2021; 18(3):715-726. doi:10.7150/ijms.50080 This issue Cite

Research Paper

Salinomycin suppresses TGF-β1-induced EMT by down-regulating MMP-2 and MMP-9 via the AMPK/SIRT1 pathway in non-small cell lung cancer

Ki-Eun Hwang^1*, Hyo-Jin Kim^4*, In-Sol Song¹, Chul Park¹, Jae Wan Jung¹, Do-Sim Park², Seon-Hee Oh³, Young-Suk Kim^4✉, Hak-Ryul Kim^1✉

1. Department of Internal Medicine, Wonkwang University, School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
2. Department of Laboratory Medicine, Wonkwang University, School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea
3. Department of Premedicine, Chosun University, School of Medicine, Gwangju 61452, Republic of Korea
4. Medical Convergence Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
^*Contributed equally

Citation:

Hwang KE, Kim HJ, Song IS, Park C, Jung JW, Park DS, Oh SH, Kim YS, Kim HR. Salinomycin suppresses TGF-β1-induced EMT by down-regulating MMP-2 and MMP-9 via the AMPK/SIRT1 pathway in non-small cell lung cancer. Int J Med Sci 2021; 18(3):715-726. doi:10.7150/ijms.50080. https://www.medsci.org/v18p0715.htm

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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: Salinomycin, TGF-β1, EMT, AMPK, SIRT, MMP, Lung cancer

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APA

Hwang, K.E., Kim, H.J., Song, I.S., Park, C., Jung, J.W., Park, D.S., Oh, S.H., Kim, Y.S., Kim, H.R. (2021). Salinomycin suppresses TGF-β1-induced EMT by down-regulating MMP-2 and MMP-9 via the AMPK/SIRT1 pathway in non-small cell lung cancer. International Journal of Medical Sciences, 18(3), 715-726. https://doi.org/10.7150/ijms.50080.

ACS

Hwang, K.E.; Kim, H.J.; Song, I.S.; Park, C.; Jung, J.W.; Park, D.S.; Oh, S.H.; Kim, Y.S.; Kim, H.R. Salinomycin suppresses TGF-β1-induced EMT by down-regulating MMP-2 and MMP-9 via the AMPK/SIRT1 pathway in non-small cell lung cancer. Int. J. Med. Sci. 2021, 18 (3), 715-726. DOI: 10.7150/ijms.50080.

NLM

CSE

Hwang KE, Kim HJ, Song IS, Park C, Jung JW, Park DS, Oh SH, Kim YS, Kim HR. 2021. Salinomycin suppresses TGF-β1-induced EMT by down-regulating MMP-2 and MMP-9 via the AMPK/SIRT1 pathway in non-small cell lung cancer. Int J Med Sci. 18(3):715-726.

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