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
Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment and are closely linked to the development and progression of various cancers, including lung cancer. LGK-974, a small molecular inhibitor of Wnt secretion, has been shown to block Wnt/β-catenin signaling and exhibit anti-inflammatory effects by reducing the expression of pro-inflammatory genes in cancer cells. While Wnt/β-catenin signaling is known to regulate TAM polarization, it remains unclear whether LGK-974 influences tumor malignancy by modulating TAMs. This study aimed to address this gap by investigating the effect of LGK-974 on TAM polarization. The results demonstrated that LGK-974 promoted M1 macrophage polarization, as evidenced by increased functional markers of M1 macrophages, and reduced M2 macrophage markers. Furthermore, the addition of Wnt3a and Wnt5a, two canonical Wnt signaling activators, reversed the reduction of M1 macrophage markers, such as mannose receptor, IL-10, and Arg1, by activating Wnt/β-catenin signaling. Conditioned media from LGK-974-modified TAMs suppressed malignant behaviors of A549 and H1299 lung cancer cells, including proliferation, colony formation, and invasion, by inhibiting Wnt/β-catenin signaling. Additionally, LGK-974-modified TAMs caused a G1/G0 cell cycle arrest in cancer cells, which could be reversed by Wnt3a/5a addition, suggesting that LGK-974 modulates the tumor microenvironment through inhibition of Wnt/β-catenin signaling in TAMs. Overall, these findings suggest that LGK-974 indirectly inhibits the malignant behavior of A549 and H1299 cells by regulating the inflammatory microenvironment and suppressing Wnt/β-catenin signaling in TAMs.