细胞周期蛋白依赖激酶6
激酶
化学
癌症研究
分子生物学
药理学
生物
蛋白激酶A
生物化学
细胞周期蛋白依赖激酶2
作者
Wei Zhou,Wenxi Wang,Yuxin Liang,Ruibin Jiang,Fensheng Qiu,Xiaorong Shao,Yang Long,Le Fang,Maowei Ni,Chunjing Yu,Yue Zhao,Weining Huang,Jiong Li,Michael Donovan,Lina Wang,Juan Ni,Dachi Wang,Ting Fu,Jianguo Feng,Xiaojia Wang,Weihong Tan,Xiaohong Fang
标识
DOI:10.1038/s41467-023-39854-y
摘要
Abstract Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6 -mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy.
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