title: The protein kinase C agonist prostratin induces differentiation of human myeloid leukemia cells and enhances cellular differentiation by chemotherapeutic agents.
abstract: As acute myeloid leukemia (AML) cells are characterized by uncontrolled self-renewal and impaired cellular differentiation, induction of terminal differentiation of leukemia cells by differentiating agents has been proposed as an attractive therapeutic strategy to treat AML. Here, we demonstrated that prostratin, a potent protein kinase C (PKC) activator, inhibited the growth of myeloid leukemia cells by a predominant G1 arrest with variable induction of apoptosis. Conversely, prostratin induced significant differentiation of AML cell lines and primary AML blasts as evidenced by morphology and immunophenotyping. The effects of prostratin were PKC dependent, and activation of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 by PKC was required for prostratin-induced cell differentiation. Consequently, prostratin reprogrammed transcriptional factor expression, and ectopic expression of c-Myc in HL-60 cells significantly eliminated prostratin-mediated cellular differentiation and cell cycle arrest, indicating an essential role for c-Myc suppression in the differentiation-inducing effects of prostratin. Finally, prostratin was able to potentiate cellular differentiation induced by chemotherapeutic agents such as Ara-C. Together, we proposed that prostratin alone or administered with other anticancer agents may be effective in differentiation therapy of AML.
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Guo-Lin
authors.initials: GL
authors.lastname: Xiong
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors.forename: He
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Yan-Feng
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Shan
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Xing
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Qing-Liang
authors.initials: QL
authors.lastname: Luo
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address: yinher2001@yahoo.com.
authors.forename: Zu-Yin
authors.initials: ZY
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address: congyw@bmi.ac.cn.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Cong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000737:chemistry* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C489427:MYC protein, human; D010703:Phorbol Esters; D016271:Proto-Oncogene Proteins c-myc; D003561:Cytarabine; C070999:prostratin; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: AML; Differentiation; Prostratin; Protein kinase C