Lw1497, an inhibitor of malate dehydrogenase, suppresses tgf-β1-induced epithelial-mesenchymal transition in lung cancer cells by downregulating slug

Hyun Ji Kim, Mi Kyung Park, Hyun Jung Byun, Minkyoung Kim, Boram Kim, Lu Yu, Tuan Minh Nguyen, Thi Ha Nguyen, Phuong Anh Do, Eun Ji Kim, Ji Hyun Kim, Enkhmend Enkhtaivan, Kyung Sung Kim, Ji Yun Jang, Gyeoung Jin Kang, Ho Lee, Misun Won, Kyeong Lee, Jungsook Cho, Chang Hoon Lee

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

LW1497 suppresses the expression of the hypoxia-inducing factor (HIF)-1α inhibiting malate dehydrogenase. Although hypoxia and HIF-1α are known to be important in cancer, LW1497 has not been therapeutically applied to cancer yet. Thus, we investigated the effect of LW1497 on the epithelial-mesenchymal transition (EMT) of lung cancer cells. A549 and H1299 lung cancer cells were induced to undergo via TGF-β1 treatment, resulting in the downregulation of E-cadherin and upregulation of N-cadherin and Vimentin concurrently with increases in the migration and invasion capacities of the cells. These effects of TGF-β1 were suppressed upon co-treatment of the cells with LW1497. An RNA-seq analysis revealed that LW1497 induced differential expression of genes related to hypoxia, RNA splicing, angiogenesis, cell migration, and metastasis in the A549 lung cancer cell lines. We confirmed the differential expression of Slug, an EMT-related transcription factor. Results from Western blotting and RT-PCR confirmed that LW1497 inhibited the expression of EMT markers and Slug. After orthotopically transplanting A549 cancer cells into mice, LW1497 was administered to examine whether the lung cancer progression was inhibited. We ob-served that LW1497 reduced the area of cancer. In addition, the results from immunohistochemical analyses showed that LW1497 downregulated EMT markers and Slug. In conclusion, LW1497 suppresses cancer progression through the inhibition of EMT by downregulating Slug.

Original languageEnglish (US)
Article number1674
JournalAntioxidants
Volume10
Issue number11
DOIs
StatePublished - Nov 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • A549
  • Epithelial-mesenchymal transition
  • Hypoxia inducible factor-α1
  • LW1497
  • Local oxygen tension
  • Malate dehydrogenase
  • Slug

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