Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Alisol B as a novel inhibitor of TβRs suppresses the growth and metastasis of non-small cell lung cancer by inhibiting TGF-β-induced epithelial-mesenchymal transition.
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Li Luyao, Wang Yuanru, Zhang Xiaoqian, Yang Xue, Li Yuqian, Lei Qiqi, Gu Simeng, Liu Shuaishuai, Xiang Liuyan, Cao Yajun, Liu Zhiyong, Li Xuejun
Аннотация
BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the major contributors to global cancer-related mortality, partly due to its aggressive metastatic behavior. TGF-β1-induced epithelial-mesenchymal transition (EMT) plays an essential role in NSCLC progression and metastasis. Alisol B (ALB), a triterpenoid derived from Alisma species, exhibits documented anti-cancer properties. However, its therapeutic efficacy and mechanisms of action against NSCLC remain poorly characterised.
PURPOSE: We investigated whether TGF-β receptors (TβRs) are involved in mediating the inhibitory effects of ALB on NSCLC growth and metastasis.
METHODS: In vitro, we assessed the impact of ALB on the proliferation, migration, and invasion of lung adenocarcinoma (LUAD) cells induced by TGF-β1 using the CCK-8, colony formation, wound healing, and transwell assays. Additionally, we utilized network pharmacology to predict the potential signaling pathways. EMT-related markers and mechanisms were assessed by Western blotting and immunofluorescence in TGF-β1-induced LUAD cells. In vivo, the LLC tumor-bearing mouse model and the B16-F10 lung metastatic mouse model were employed to investigate the effect of ALB on the tumor growth and lung metastasis. H&E staining was used to assess histopathology. We then employed molecular docking, molecular dynamics simulation (MD simulation), surface plasmon resonance (SPR), drug Affinity Responsive Target Stability (DARTS), and cellular thermal shift assay (CETSA) to investigate the interaction between ALB and TGF-β receptors. Cell transfection was used to verify the effects of ALB.
RESULTS: This study showed that ALB suppressed TGF-β1-induced proliferation, migration, invasion, and EMT process of LUAD cells, and inhibited tumor growth and lung metastasis in vivo. A suite of techniques, including molecular docking, MD simulation, SPR, DARTS, and CETSA, collectively demonstrated that ALB at pharmacological concentrations could directly interact with the ATP-binding sites within the kinase domains of both TGF-β receptor type-1 (TGFβR1) and TGF-β receptor type-2 (TGFβR2), and then promotes the proteasomal degradation of TGFβR2, leading to reduced phosphorylation of TGFβR1 and consequent suppression of both canonical (TGF-β/Smad) and non-canonical (MAPK and PI3K/Akt) signaling pathways. Moreover, the inhibitory effects of ALB on migration, invasion, and the EMT process were significantly diminished in A549 cells with TGFβR1 and TGFβR2 knocked down, indicating that ALB effectively abrogated the kinase activity of TGFβR1 and TGFβR2.
CONCLUSION: Our findings demonstrate that ALB functions as a novel inhibitor of TβRs, effectively suppressing tumor growth and lung metastasis by inhibiting the EMT process both in vitro and in vivo.
PURPOSE: We investigated whether TGF-β receptors (TβRs) are involved in mediating the inhibitory effects of ALB on NSCLC growth and metastasis.
METHODS: In vitro, we assessed the impact of ALB on the proliferation, migration, and invasion of lung adenocarcinoma (LUAD) cells induced by TGF-β1 using the CCK-8, colony formation, wound healing, and transwell assays. Additionally, we utilized network pharmacology to predict the potential signaling pathways. EMT-related markers and mechanisms were assessed by Western blotting and immunofluorescence in TGF-β1-induced LUAD cells. In vivo, the LLC tumor-bearing mouse model and the B16-F10 lung metastatic mouse model were employed to investigate the effect of ALB on the tumor growth and lung metastasis. H&E staining was used to assess histopathology. We then employed molecular docking, molecular dynamics simulation (MD simulation), surface plasmon resonance (SPR), drug Affinity Responsive Target Stability (DARTS), and cellular thermal shift assay (CETSA) to investigate the interaction between ALB and TGF-β receptors. Cell transfection was used to verify the effects of ALB.
RESULTS: This study showed that ALB suppressed TGF-β1-induced proliferation, migration, invasion, and EMT process of LUAD cells, and inhibited tumor growth and lung metastasis in vivo. A suite of techniques, including molecular docking, MD simulation, SPR, DARTS, and CETSA, collectively demonstrated that ALB at pharmacological concentrations could directly interact with the ATP-binding sites within the kinase domains of both TGF-β receptor type-1 (TGFβR1) and TGF-β receptor type-2 (TGFβR2), and then promotes the proteasomal degradation of TGFβR2, leading to reduced phosphorylation of TGFβR1 and consequent suppression of both canonical (TGF-β/Smad) and non-canonical (MAPK and PI3K/Akt) signaling pathways. Moreover, the inhibitory effects of ALB on migration, invasion, and the EMT process were significantly diminished in A549 cells with TGFβR1 and TGFβR2 knocked down, indicating that ALB effectively abrogated the kinase activity of TGFβR1 and TGFβR2.
CONCLUSION: Our findings demonstrate that ALB functions as a novel inhibitor of TβRs, effectively suppressing tumor growth and lung metastasis by inhibiting the EMT process both in vitro and in vivo.