Cyclin-dependent kinase 1 as a potential target for lycorine against hepatocellular carcinoma

• Published in: Biochemical pharmacology Vol. 193; p. 114806
• Main Authors: Yin, Shuangshuang, Yang, Shenshen, Luo, Yanming, Lu, Jia, Hu, Gaoyong, Wang, Kailong, Shao, Yingying, Zhou, Shiyue, Koo, Sangho, Qiu, Yuling, Wang, Tao, Yu, Haiyang
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.11.2021
• Subjects: Amaryllidaceae Alkaloids - chemistry; Amaryllidaceae Alkaloids - pharmacology; Amaryllidaceae Alkaloids - therapeutic use; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Carcinoma, Hepatocellular - drug therapy; CDC2 Protein Kinase - antagonists & inhibitors; CDC2 Protein Kinase - genetics; CDC2 Protein Kinase - metabolism; CDK1; Cell Line, Tumor; Cell senescence; Cellular Senescence; Cyclin B1 - genetics; Cyclin B1 - metabolism; Cyclin B2 - genetics; Cyclin B2 - metabolism; Drug Delivery Systems; Gene Expression Regulation, Enzymologic - drug effects; HCC; Humans; Liver Neoplasms - drug therapy; Lycorine; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Phenanthridines - chemistry; Phenanthridines - pharmacology; Phenanthridines - therapeutic use; Xenograft Model Antitumor Assays; PBS; BCA; DMSO; HCC; DAPI; DARTS; Lycorine; PVDF; Ly; CETSA; CCNB2; DMEM; BSA; CCNB1; Cell senescence; PMSF; FBS; CDK1; Cancer
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2021.114806

[Display omitted] The pathological changes and possible underlying molecular mechanisms of hepatocellular carcinoma (HCC) are currently unclear. Effective treatment of this pathological state remains a challenge. The purpose of this study is to obtain some key genes with diagnostic and prognostic meaning and to identify potential therapeutic agents for HCC treatment. Here, CDK1, CCNB1 and CCNB2 were found to be highly expressed in HCC patients and accompanied by poor prognosis, and knockdown of them by siRNA drastically induced autophagy and senescence in hepatoma cells. Simultaneously, the anti-HCC effect of lycorine was comparable to that of interfering with these three genes, and lycorine significantly promoted the decrease both in protein and mRNA expression of CDK1. Molecular validation mechanistically demonstrated that lycorine might attenuate the degradation rate of CDK1 via interaction with it, which had been confirmed by cellular thermal shift assay and drug affinity responsive targets stability assay. Taken together, these findings suggested that CDK1, CCNB1 and CCNB2 could be regarded as potential diagnostic and prognostic biomarkers for HCC, and CDK1 might serve as a promising therapeutic target for lycorine against HCC.