期刊
INTERNATIONAL JOURNAL OF HEMATOLOGY
卷 102, 期 5, 页码 558-568出版社
SPRINGER JAPAN KK
DOI: 10.1007/s12185-015-1858-1
关键词
Acute lymphoblastic leukemia; Rapamycin; p14; p15; p57; mTOR
类别
资金
- Ph.D. Programs Foundation of the Ministry of Education of China [20132307110022]
- Science and Technology project of Heilongjiang Province [GC12C303-4]
- Foundation for the Returned Overseas Chinese Scholars of Heilongjiang Province [LCO7C22]
- Application Technology Research and Development Project of the Harbin Science and Technology Bureau [2014RFQGJ145]
- Science Foundation of the First Affiliated Hospital at Harbin Medical University [2013B14]
The aim of the present study was to investigate the effects of rapamycin and its underlying mechanisms on acute lymphoblastic leukemia (ALL) cells. We found that the p14, p15, and p57 genes were not expressed in ALL cell lines (Molt-4 and Nalm-6) and adult ALL patients, whereas mTOR, 4E-BP1, and p70S6K were highly expressed. In Molt-4 and Nalm-6 cells exposed to rapamycin, cell viability decreased and the cell cycle was arrested at the G1/S phase. Rapamycin restored p14, p15, and p57 gene expression through demethylation of the promoters of these genes. As expected, rapamycin also increased p14 and p15 protein expression in both Molt-4 and Nalm-6 cells, as well as p57 protein expression in Nalm-6 cells. Rapamycin additionally decreased mTOR and p70S6K mRNA levels, as well as p70S6K and p-p70S6K protein levels. However, depletion of mTOR by siRNA did not alter the expression and promoter methylation states of p14, p15, and p57. These results indicate that the inhibitory effect of rapamycin may be due mainly to increased p14, p15, and p57 expression via promoter demethylation and decreased mTOR and p70S6K expression in ALL cell lines. These results suggest a potential role for rapamycin in the treatment of adult ALL.
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