生物
细胞凋亡
细胞周期
阿霉素
细胞生物学
细胞
癌细胞
N-Myc公司
细胞培养
作者
Sanhita Mitra,Somsundar Veppil Muralidharan,Mirco Di Marco,Prasanna Kumar Juvvuna,Subazini Thankaswamy Kosalai,Silke Reischl,Daniel Jachimowicz,Santhilal Subhash,Ivan Raimondi,Leo Kurian,Maite Huarte,Per Kogner,Matthias Fischer,John Inge Johnsen,Tanmoy Mondal,Chandrasekhar Kanduri
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-03-15
卷期号:81 (6): 1457-1471
被引量:6
标识
DOI:10.1158/0008-5472.can-19-3499
摘要
Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for high-risk neuroblastoma patients.
科研通智能强力驱动
Strongly Powered by AbleSci AI