Table_1_RRM2 Mediates the Anti-Tumor Effect of the Natural Product Pectolinarigenin on Glioblastoma Through Promoting CDK1 Protein Degradation by Increasing Autophagic Flux.docx

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.

天然产物柳穿鱼黄素（pectolinarigenin）具有抗炎及抗肿瘤活性，可发挥多种生物学功能，尤其在自噬与细胞周期调控中作用显著。然而，柳穿鱼黄素对胶质母细胞瘤（GBM）的抗肿瘤效应尚未明确。本研究发现，柳穿鱼黄素可通过抑制核糖核苷酸还原酶亚基M2（RRM2），抑制胶质母细胞瘤细胞增殖、增强自噬流并诱导细胞周期阻滞，该效应可被RRM2过表达质粒逆转。此外，柳穿鱼黄素通过提升自噬流，经自噬溶酶体依赖通路促进RRM2蛋白降解。敲低RRM2可通过增强自噬流，经自噬溶酶体依赖通路促进细胞周期蛋白依赖性激酶1（CDK1）蛋白降解，进而通过诱导G2/M期细胞周期阻滞抑制胶质母细胞瘤细胞增殖。临床数据分析显示，胶质瘤患者体内RRM2的表达水平与总生存期呈负相关。综上，柳穿鱼黄素可通过抑制RRM2增强自噬流，依赖自噬溶酶体通路促进CDK1蛋白降解，最终通过诱导G2/M期细胞周期阻滞抑制胶质母细胞瘤细胞增殖；RRM2或可成为GBM患者潜在的治疗靶点及预后预测生物标志物。