title: Rapamycin restores p14, p15 and p57 expression and inhibits the mTOR/p70S6K pathway in acute lymphoblastic leukemia cells.
abstract: 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.
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Huibo
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Kong
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Cui
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Ren
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Shengjin
authors.initials: S
authors.lastname: Fan
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Sun
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Rongyi
authors.initials: R
authors.lastname: Cao
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China. yinghualihmu@126.com.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Medicine, The First Affiliated Hospital, Harbin Medical University, 23 Youzheng Street, Nan Gang District, Harbin, 150001, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000096:biosynthesis*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D015513:Oncogene Proteins / Q000096:biosynthesis*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C401561:CDK2AP2 protein, human; C493964:CDKN1C protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050761:Cyclin-Dependent Kinase Inhibitor p57; D015513:Oncogene Proteins; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Acute lymphoblastic leukemia; Rapamycin; mTOR; p14; p15; p57