Study On The Mechanism Of SHIN1 Inhibiting Lung Cancer Cell Proliferation By Blocking Cell Cycle Operation

Lung cancer is the cancer with the highest incidence and mortality in China,which seriously endangers the life and health of Chinese people.Metabolic reprogramming is one of the characteristics of cancer.Targeting metabolic reprogramming to develop antitumor drugs is a promising strategy for cancer therapy.Abnormal metabolism of serine is an important feature of tumor metabolic reprogramming,which provides the precursor of synthesis of biological macromolecules for cancer cells and participates in the process of methylation modification,thus promoting the development of tumor.SHIN1 is a specific inhibitor of serine catabolic rate-limiting enzyme,Serine hydroxymethyltransferase SHMT(SHMT1 and SHMT2).Studies have shown that SHIN1 has a significant inhibitory effect on the occurrence and development of hematological T-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma.But there have been no studies of SHIN1 in solid tumors,In this study,it was found that SHIN1 treatment significantly inhibited the proliferation of cancer cells in lung cancer,and the cell cycle of lung cancer was arrested in G2/M phase.However,normal bronchial epithelial cells showed low sensitivity to SHIN1 and only showed inhibitory effect on cell proliferation at high concentration.Further mechanism studies suggest that SHIN1 regulates the cell cycle by accelerating the degradation of CDK1 protein.In addition,it was found that CDK1 interacts with E3 ubiquitin ligase NEDD4 L through immunocoprecipitation,and NEDD4 L mediates the degradation of CDK1 through ubiquitination.Therefore,our study for the first time found that SHIN1 can inhibit the proliferation of lung cancer cells,revealing the molecular mechanism that SHIN1 blocks the cell cycle by promoting NEDD4L-mediated CDK1 ubiquitination degradation,and thus providing a theoretical basis for targeted serine metabolism therapy for cell lung cancer.