Tissue & cell · 2025
IL-8/CXCR2 mediates resistance to apatinib through PI3K/AKT and vasculogenic mimicry in gastric cancer cells.
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Fan Yan-Wen, Liu Ya-Xian, Jiang Ning-Jing, Qian Si-Tong, Huang Xin-En, Wu Jia-Qi, He Ming-Fang
Аннотация
BACKGROUND: Resistance to apatinib remains a major barrier to achieving favorable outcomes in patients with gastric cancer (GC). This study aimed to identify key molecular targets associated with apatinib resistance and to elucidate the underlying mechanisms.
METHODS: By analyzing datasets related to anti-angiogenic therapies and treatment outcomes, we identified the hub gene associated with apatinib resistance. Its correlation with resistance was validated through gene manipulation in GC cells, alongside a series of in vitro and in vivo studies. Protein expression profiling was further performed to explore the underline mechanisms.
RESULTS: Our findings revealed a substantial association between IL-8 expression and resistance to anti-angiogenic therapy. Exogenous IL-8 treatment increased apatinib resistance in AGS cells. CXCR2 knockdown enhanced apatinib sensitivity while simultaneously inhibiting the migratory, invasive, and colony-forming capacities of AGS cells in vitro, as well as tumor growth and metastasis in vivo. Conversely, CXCR2 overexpression promoted resistance and aggressive phenotypes. Moreover, CXCR2 expression was found to be essential for vasculogenic mimicry (VM) formation in AGS cells. Importantly, knockdown or overexpression of CXCR2 modulated the expressions of p-PI3K, p-AKT, and VM-related proteins, including MMP2, MMP-14, VEGFR2, and PECAM1.
CONCLUSION: These results indicate that IL-8/CXCR2 promotes apatinib resistance in human GC by activating the PI3K/AKT pathway and inducing VM. This work highlights a therapeutic strategy to improve apatinib efficacy and patient prognosis in GC.
METHODS: By analyzing datasets related to anti-angiogenic therapies and treatment outcomes, we identified the hub gene associated with apatinib resistance. Its correlation with resistance was validated through gene manipulation in GC cells, alongside a series of in vitro and in vivo studies. Protein expression profiling was further performed to explore the underline mechanisms.
RESULTS: Our findings revealed a substantial association between IL-8 expression and resistance to anti-angiogenic therapy. Exogenous IL-8 treatment increased apatinib resistance in AGS cells. CXCR2 knockdown enhanced apatinib sensitivity while simultaneously inhibiting the migratory, invasive, and colony-forming capacities of AGS cells in vitro, as well as tumor growth and metastasis in vivo. Conversely, CXCR2 overexpression promoted resistance and aggressive phenotypes. Moreover, CXCR2 expression was found to be essential for vasculogenic mimicry (VM) formation in AGS cells. Importantly, knockdown or overexpression of CXCR2 modulated the expressions of p-PI3K, p-AKT, and VM-related proteins, including MMP2, MMP-14, VEGFR2, and PECAM1.
CONCLUSION: These results indicate that IL-8/CXCR2 promotes apatinib resistance in human GC by activating the PI3K/AKT pathway and inducing VM. This work highlights a therapeutic strategy to improve apatinib efficacy and patient prognosis in GC.