International urology and nephrology · 2025
ZSTK474 suppresses bladder cancer cell migration and invasion via PI3K/Akt/Girdin pathway: an in vitro study.
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Song Zhaoxia, Wang Ying, Yu Chunhu, Sha Kefu, Zhao Mingjun, Liu Tiejun
Аннотация
OBJECTIVE: Metastasis is the leading cause of mortality in bladder cancer (BC). This study investigates the antimetastatic potential of ZSTK474, a phosphatidylinositol 3-kinase (PI3K) inhibitor developed for solid tumor therapy. Specifically, the study evaluates the effects of ZSTK474 on tumor cell migration and invasion, two critical processes in metastasis using in vitro assays.
METHODS: Human BC cell lines, CAL29 and BIU87, were treated with ZSTK474 at concentrations of 0, 0.05, 0.25, and 1.5 µM. Cell proliferation was assessed using the BrdU incorporation assay. Migration capacity was evaluated through scratch and Transwell migration assays, while invasion potential was determined using a Matrigel-coated Transwell invasion assay. Western blotting was performed to analyze the expression levels of Girdin, phosphorylated Girdin (p-Girdin), phosphorylated Akt (p-Akt), and PI3K.
RESULTS: Treatment with ZSTK474 significantly inhibited BC cell proliferation, as demonstrated by the BrdU incorporation assay. Additionally, a substantial reduction in cell invasion was observed in the Transwell invasion assay (p < 0.01). Western blot analysis revealed that ZSTK474 suppressed the phosphorylation of Girdin in BC cells. Higher concentrations of ZSTK474 were associated with decreased relative expression levels of Girdin, p-Girdin, p-Akt, and PI3K. However, no significant inhibitory effect on Akt expression was detected following ZSTK474 treatment. Although total Akt protein levels remained unchanged, whereas phosphorylated Akt (p-Akt) was significantly reduced.
CONCLUSION: The findings of this study suggest that ZSTK474 effectively inhibits bladder cancer cell migration and invasion by suppressing key signaling pathways involved in metastasis. Specifically, ZSTK474 reduces the phosphorylation of Girdin, an Akt substrate implicated in tumor migration and invasion. These results provide further evidence supporting the therapeutic potential of ZSTK474 in mitigating metastatic progression in bladder cancer.
METHODS: Human BC cell lines, CAL29 and BIU87, were treated with ZSTK474 at concentrations of 0, 0.05, 0.25, and 1.5 µM. Cell proliferation was assessed using the BrdU incorporation assay. Migration capacity was evaluated through scratch and Transwell migration assays, while invasion potential was determined using a Matrigel-coated Transwell invasion assay. Western blotting was performed to analyze the expression levels of Girdin, phosphorylated Girdin (p-Girdin), phosphorylated Akt (p-Akt), and PI3K.
RESULTS: Treatment with ZSTK474 significantly inhibited BC cell proliferation, as demonstrated by the BrdU incorporation assay. Additionally, a substantial reduction in cell invasion was observed in the Transwell invasion assay (p < 0.01). Western blot analysis revealed that ZSTK474 suppressed the phosphorylation of Girdin in BC cells. Higher concentrations of ZSTK474 were associated with decreased relative expression levels of Girdin, p-Girdin, p-Akt, and PI3K. However, no significant inhibitory effect on Akt expression was detected following ZSTK474 treatment. Although total Akt protein levels remained unchanged, whereas phosphorylated Akt (p-Akt) was significantly reduced.
CONCLUSION: The findings of this study suggest that ZSTK474 effectively inhibits bladder cancer cell migration and invasion by suppressing key signaling pathways involved in metastasis. Specifically, ZSTK474 reduces the phosphorylation of Girdin, an Akt substrate implicated in tumor migration and invasion. These results provide further evidence supporting the therapeutic potential of ZSTK474 in mitigating metastatic progression in bladder cancer.