2. Academic Validation
  3. The protein kinase C agonist prostratin induces differentiation of human myeloid leukemia cells and enhances cellular differentiation by chemotherapeutic agents

The protein kinase C agonist prostratin induces differentiation of human myeloid leukemia cells and enhances cellular differentiation by chemotherapeutic agents

  • Cancer Lett. 2015 Jan 28;356(2 Pt B):686-96. doi: 10.1016/j.canlet.2014.10.018.
Xing Shen 1,  Guo-Lin Xiong 1,  Yu Jing 2,  He Xiao 3,  Yu Cui 1,  Yan-Feng Zhang 1,  Ya-Jun Shan 1,  Shuang Xing 1,  Meng Yang 1,  Xiao-Lan Liu 1,  Bo Dong 1,  Li-Sheng Wang 4,  Qing-Liang Luo 1,  Zu-Yin Yu 5,  Yu-Wen Cong 6
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
  • 2 Department of Hematology, Chinese PLA General Hospital, Beijing, China.
  • 3 Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
  • 4 Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, China.
  • 5 Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address: [email protected].
  • 6 Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address: [email protected].
PMID: 25449427 DOI: 10.1016/j.canlet.2014.10.018
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.

Keywords

AML; Differentiation; Prostratin; Protein kinase C.

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