title: Down-regulation of BMI-1 cooperates with artemisinin on growth inhibition of nasopharyngeal carcinoma cells.
abstract: Artemisinin and its derivatives are well known antimalaria drugs, particularly useful for the treatment of infection of Plasmodium falciparum malaria parasites resistant to traditional antimalarial pharmaceuticals. Artemisinin has inhibitory effects on cancer cell growth and anti-angiogenetic activity, including many drug- and radiation-resistant cancer cell lines. Moloney murine leukemia virus insertion site 1 (BMI-1) has been shown to regulate proliferation by inhibiting p16(ink4a) transcription. It is well known that BMI-1 over-expression was found in nasopharyngeal carcinoma cell lines and correlated with advanced invasive stage of the tumor progression and poor prognosis. In the present investigation, we analyzed the inhibitory effects of artemisinin on proliferation of nasopharyngeal carcinoma cell lines (CNE-1 and CNE-2, well-differentiated cells, and poorly differentiated cells). We demonstrated that artemisinin induced G1 cell cycle arrest in CNE-1 and CNE-2 cells. Artemisinin inhibited BMI-1 both in protein and transcript levels. BMI-1 knockdown made the cells more sensitive to artemisinin with an increase in G1 phase, but over-expression of BMI-1 partially reversed the artemisinin-induced G1 cell cycle arrest. Depletion of BMI-1 was able to intensifying the increment of p16 and the reduction of CDK4 induced by artemisinin. In addition, over-expression of BMI-1 was capable of attenuating the increasing p16 and decreasing CDK4 in cells treated with artemisinin. Taking together, the BMI1-p16/CDK4 axis was involved in the artemisinin-driven G1 arrest in nasopharyngeal carcinoma cells, and these results indicated that a potential treatment that the combination of artemisinin and BMI-1 downregulation could enhance the growth inhibitory affects on nasopharyngeal carcinoma cells.
authors: Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong, People's Republic of China.
authors: Jing
authors: J
authors: Wu
authors: Dong
authors: D
authors: Hu
authors: Guang
authors: G
authors: Yang
authors: Junyi
authors: J
authors: Zhou
authors: Changfu
authors: C
authors: Yang
authors: Yun
authors: Y
authors: Gao
authors: Zhenyu
authors: Z
authors: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; C069077:BMI1 protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C031327:artemisinin; D063150:Polycomb Repressive Complex 1; D018844:Cyclin-Dependent Kinases