1. Molecular mechanism of G1 arrest and cellular senescence induced by LEE011, a novel CDK4/CDK6 inhibitor, in leukemia cells
- Author
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Jian Pan, Jian Wang, Na-Na Wang, Xing Feng, Yan-Fang Tao, Zhi-Heng Li, Yunyun Xu, Yi Wu, Guang-Hui Qian, Li-Xiao Xu, Mei Li, Xiaolu Li, Jun Lu, Junli Ren, Wei-Wei Du, Wei-Qi He, Fang Fang, Yanhong Li, Yi-Ping Li, and Shaoyan Hu
- Subjects
0301 basic medicine ,Senescence ,Cancer Research ,Cell ,Biology ,Cellular senescence ,Arraystar Human LncRNA array ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Genetics ,CDK4/6 ,LEE011 ,Propidium iodide ,Acute leukemia ,Leukemia ,Cell growth ,Cell cycle ,medicine.disease ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cyclin-dependent kinase 6 ,Primary Research - Abstract
Background Overexpression of cyclin D1 dependent kinases 4 and 6 (CDK4/6) is a common feature of many human cancers including leukemia. LEE011 is a novel inhibitor of both CDK4 and 6. To date, the molecular function of LEE011 in leukemia remains unclear. Methods Leukemia cell growth and apoptosis following LEE011 treatment was assessed through CCK-8 and annexin V/propidium iodide staining assays. Cell senescence was assessed by β-galactosidase staining and p16INK4a expression analysis. Gene expression profiles of LEE011 treated HL-60 cells were investigated using an Arraystar Human LncRNA array. Gene ontology and KEGG pathway analysis were then used to analyze the differentially expressed genes from the cluster analysis. Results Our studies demonstrated that LEE011 inhibited proliferation of leukemia cells and could induce apoptosis. Hoechst 33,342 staining analysis showed DNA fragmentation and distortion of nuclear structures following LEE011 treatment. Cell cycle analysis showed LEE011 significantly induced cell cycle G1 arrest in seven of eight acute leukemia cells lines, the exception being THP-1 cells. β-Galactosidase staining analysis and p16INK4a expression analysis showed that LEE011 treatment can induce cell senescence of leukemia cells. LncRNA microarray analysis showed 2083 differentially expressed mRNAs and 3224 differentially expressed lncRNAs in LEE011-treated HL-60 cells compared with controls. Molecular function analysis showed that LEE011 induced senescence in leukemia cells partially through downregulation of the transcriptional expression of MYBL2. Conclusions We demonstrate for the first time that LEE011 treatment results in inhibition of cell proliferation and induction of G1 arrest and cellular senescence in leukemia cells. LncRNA microarray analysis showed differentially expressed mRNAs and lncRNAs in LEE011-treated HL-60 cells and we demonstrated that LEE011 induces cellular senescence partially through downregulation of the expression of MYBL2. These results may open new lines of investigation regarding the molecular mechanism of LEE011 induced cellular senescence. Electronic supplementary material The online version of this article (doi:10.1186/s12935-017-0405-y) contains supplementary material, which is available to authorized users.
- Published
- 2017