Polyphyllin I ameliorates gefitinib resistance and inhibits the VEGF/VEGFR2/p38 pathway by targeting HIF-1a in lung adenocarcinoma.
Phytomedicine
; 129: 155690, 2024 Jul.
Article
en En
| MEDLINE
| ID: mdl-38761523
ABSTRACT
BACKGROUND:
Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive.PURPOSE:
To evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism.METHODS:
CCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance.RESULTS:
PPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC50 at 2.0 µM). Significantly, treatment with PPI at 1.0 µM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL.CONCLUSIONS:
We present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Resistencia a Antineoplásicos
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Receptor 2 de Factores de Crecimiento Endotelial Vascular
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Factor A de Crecimiento Endotelial Vascular
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Diosgenina
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Subunidad alfa del Factor 1 Inducible por Hipoxia
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Gefitinib
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Adenocarcinoma del Pulmón
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Neoplasias Pulmonares
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Ratones Desnudos
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Phytomedicine
Asunto de la revista:
TERAPIAS COMPLEMENTARES
Año:
2024
Tipo del documento:
Article
País de afiliación:
China