RRM2 Mediates the Anti-Tumor Effect of the Natural Product Pectolinarigenin on Glioblastoma Through Promoting CDK1 Protein Degradation by Increasing Autophagic Flux.
RRM2 Mediates the Anti-Tumor Effect of the Natural Product Pectolinarigenin on Glioblastoma Through Promoting CDK1 Protein Degradation by Increasing Autophagic Flux.
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DOI：
10.3389/fonc.2022.887294
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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天然产物pectolinarigenin具有抗炎活性和抗肿瘤作用，并表现出不同的生物学功能，特别是在自噬和细胞周期调节方面。然而，pectolinarigenin对胶质母细胞瘤（GBM）的抑制作用尚不清楚。在本研究中，我们发现，pectolinarigenin抑制胶质母细胞瘤增殖，增加自噬流量，并通过抑制核糖核苷酸还原酶亚基M2（RRM 2）诱导细胞周期阻滞，这可以逆转RRM 2过表达质粒。此外，pectolinarigenin通过增加自噬流促进RRM 2蛋白通过自溶体依赖性途径降解。RRM 2基因敲低可通过增加自噬流，促进CDK 1蛋白通过自溶体依赖性途径降解，从而诱导G2/M期细胞阻滞，抑制胶质母细胞瘤的增殖。临床资料分析显示，胶质瘤患者RRM 2表达与总生存期呈负相关。因此，果胶银合欢素通过抑制RRM 2，增加自噬流量，促进依赖于自溶酶体途径的CDK 1蛋白降解，从而诱导G2/M期细胞阻滞，抑制胶质母细胞瘤细胞增殖，RRM 2可能成为胶质母细胞瘤患者潜在的治疗靶点和预后预测生物标志物。
The natural product pectolinarigenin exerts anti-inflammatory activity and anti-tumor effects, and exhibits different biological functions, particularly in autophagy and cell cycle regulation. However, the antineoplastic effect of pectolinarigenin on glioblastoma (GBM) remains unclear. In the present study, we found that pectolinarigenin inhibits glioblastoma proliferation, increases autophagic flux, and induces cell cycle arrest by inhibiting ribonucleotide reductase subunit M2 (RRM2), which can be reversed by RRM2 overexpression plasmid. Additionally, pectolinarigenin promoted RRM2 protein degradation via autolysosome-dependent pathway by increasing autophagic flow. RRM2 knockdown promoted the degradation of CDK1 protein through autolysosome-dependent pathway by increasing autophagic flow, thereby inhibiting the proliferation of glioblastoma by inducing G2/M phase cell cycle arrest. Clinical data analysis revealed that RRM2 expression in glioma patients was inversely correlated with the overall survival. Collectively, pectolinarigenin promoted the degradation of CDK1 protein dependent on autolysosomal pathway through increasing autophagic flux by inhibiting RRM2, thereby inhibiting the proliferation of glioblastoma cells by inducing G2/M phase cell cycle arrest, and RRM2 may be a potential therapeutic target and a prognosis and predictive biomarker in GBM patients.
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