中国药理学通报2025，Vol.41Issue(12)：2297-2305,9.DOI:10.12360/CPB202504027
蛋白激酶D抑制剂CRT0066101通过抑制PI3K/AKT信号通路促进肝癌细胞凋亡和自噬抑制肿瘤
Protein kinase D inhibitor CRT0066101 suppresses tumor growth by inhibiting the PI3K/AKT signaling pathway to promote apoptosis and autophagy in hepatocellular carcinoma cells
摘要
Abstract
Aim To investigate the inhibitory effect of the protein kinase D(PKD)-specific inhibitor CRT0066101 on hepatocellular carcinoma(HCC)and its underlying molecular mechanisms,providing new theoretical insights and therapeutic strategies for targe-ted HCC treatment.Methods HCC cell lines were treated with varying concentrations of CRT0066101.The inhibitory effects on cell proliferation were assessed using the CCK-8 assay,colony formation assay,and EdU staining.The impact on cell migration and inva-sion was evaluated through wound-healing assays and Transwell migration and invasion assays.was employed toThe effects of CRT0066101 on the phosphorylation levels of PKD and key proteins in the downstream PI3K/AKT signaling pathway were analyzed using Western blot.Additionally,the drug's regulatory effects on apoptosis and autophagy in HCC cells were examined using Western blot,flow cytometry,and the mRFP-GFP-LC3 dual-fluorescence reporter system.Results CRT0066101 significantly inhibited the pro-liferation,migration and invasion of HCC cells.West-ern blotting results demonstrated that CRT0066101 dose-dependently suppressed the phosphorylation of PKD family proteins and downregulated the activation of the PI3K/AKT signaling pathway.Furthermore,CRT0066101 treatment upregulated the expression of the pro-apoptotic protein Bax while downregulating the anti-apoptotic protein Bcl-2.It also markedly increased the expression levels of autophagy marker proteins Bec-lin-1 and LC3B-Ⅱ,suggesting that the drug simulta-neously induced apoptosis and autophagy in HCC cells.Conclusions CRT0066101 specifically inhibits PKD activity,blocks the PI3K/AKT signaling path-way,suppresses HCC cell proliferation and metastasis,and induces apoptosis and autophagy.These findings indicate that CRT0066101 is a promising small-mole-cule inhibitor for targeted HCC therapy with potential clinical applications.关键词
肝癌/CRT0066101/自噬/凋亡/抑制剂/蛋白激酶DKey words
hepatocellular carcinoma/CRT0066101/autophagy/apoptosis/inhibitor/protein kinase D分类
医药卫生引用本文复制引用
邓浩华,唐宝元,谢蓓,李林静..蛋白激酶D抑制剂CRT0066101通过抑制PI3K/AKT信号通路促进肝癌细胞凋亡和自噬抑制肿瘤[J].中国药理学通报,2025,41(12):2297-2305,9.基金项目
国家自然科学基金资助项目(No 2272405、82060531、81602622) （No 2272405、82060531、81602622）
甘肃省科技厅联合科研基金(No 23JRRA1503) （No 23JRRA1503）
甘肃省重点研发计划(No 25YFFA052) （No 25YFFA052）
兰州市人才创新创业项目(No 2023RC28) （No 2023RC28）
甘肃省卫生行业优秀青年人才科研专项(No GSWSQN2022-02) （No GSWSQN2022-02）
兰州市城关区人才创新创业项目(No 2024-rc-2) （No 2024-rc-2）
兰大二院萃英科技创新计划项目(No CY2024-ZD-01) （No CY2024-ZD-01）
甘肃省自然科学基金资助项目(No 24JRRA431) （No 24JRRA431）
