Open Access

Porcupine inhibitor LGK‑974 inhibits Wnt/β‑catenin signaling and modifies tumor‑associated macrophages resulting in inhibition of the malignant behaviors of non‑small cell lung cancer cells

  • Authors:
    • Yang Tang
    • Maoyan Jiang
    • Anping Chen
    • Wendong Qu
    • Xu Han
    • Jiebin Zuo
    • Gang Xu
    • Yongxiang Song
    • Cheng Chen
    • Xixian Ke
  • View Affiliations

  • Published online on: June 2, 2021     https://doi.org/10.3892/mmr.2021.12189
  • Article Number: 550
  • Copyright: © Tang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tumor‑associated macrophages (TAMs) are critical components of the tumor microenvironment that are tightly associated with malignancies in human cancers, including lung cancer. LGK‑974, a small molecular inhibitor of Wnt secretion, was reported to block Wnt/β‑catenin signaling and exert anti‑inflammatory effects by suppressing pro‑inflammatory gene expression in cancer cells. Although it was reported that Wnt/β‑catenin was critical in regulating TAMs, it is still largely unknown whether LGK‑974 regulates tumor malignancies by regulating TAMs. The present study firstly verified that the polarization of TAMs was regulated by LGK‑974. LGK‑974 increased M1 macrophage functional markers and decreased M2 macrophage functional markers. The addition of Wnt3a and Wnt5a, two canonical Wnt signaling inducers, reversed the decrease in M1 macrophage functional markers, including mannose receptor, IL‑10 and Arg1, by activating Wnt/β‑catenin signaling. Conditioned medium from LGK‑974‑modified TAMs inhibited the malignant behaviors in A549 and H1299 cells, including proliferation, colony formation and invasion, by blocking Wnt/β‑catenin signaling. LGK‑974‑modified TAMs blocked the cell cycle at the G1/G0 phase, which was reversed by the addition of Wnt3a/5a, indicating that LGK‑974 regulates the microenvironment by blocking Wnt/β‑catenin signaling. Taken together, the results indicate that LGK‑974 indirectly inhibited the malignant behaviors of A549 and H1299 cells by regulating the inflammatory microenvironment by inhibiting Wnt/β‑catenin signaling in TAMs.
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August-2021
Volume 24 Issue 2

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Spandidos Publications style
Tang Y, Jiang M, Chen A, Qu W, Han X, Zuo J, Xu G, Song Y, Chen C, Ke X, Ke X, et al: Porcupine inhibitor LGK‑974 inhibits Wnt/β‑catenin signaling and modifies tumor‑associated macrophages resulting in inhibition of the malignant behaviors of non‑small cell lung cancer cells. Mol Med Rep 24: 550, 2021
APA
Tang, Y., Jiang, M., Chen, A., Qu, W., Han, X., Zuo, J. ... Ke, X. (2021). Porcupine inhibitor LGK‑974 inhibits Wnt/β‑catenin signaling and modifies tumor‑associated macrophages resulting in inhibition of the malignant behaviors of non‑small cell lung cancer cells. Molecular Medicine Reports, 24, 550. https://doi.org/10.3892/mmr.2021.12189
MLA
Tang, Y., Jiang, M., Chen, A., Qu, W., Han, X., Zuo, J., Xu, G., Song, Y., Chen, C., Ke, X."Porcupine inhibitor LGK‑974 inhibits Wnt/β‑catenin signaling and modifies tumor‑associated macrophages resulting in inhibition of the malignant behaviors of non‑small cell lung cancer cells". Molecular Medicine Reports 24.2 (2021): 550.
Chicago
Tang, Y., Jiang, M., Chen, A., Qu, W., Han, X., Zuo, J., Xu, G., Song, Y., Chen, C., Ke, X."Porcupine inhibitor LGK‑974 inhibits Wnt/β‑catenin signaling and modifies tumor‑associated macrophages resulting in inhibition of the malignant behaviors of non‑small cell lung cancer cells". Molecular Medicine Reports 24, no. 2 (2021): 550. https://doi.org/10.3892/mmr.2021.12189