The protein kinase C agonist prostratin induces differentiation of human myeloid leukemia cells and enhances cellular differentiation by chemotherapeutic agents. Issue 2 (28th January 2015)

• Record Type: Journal Article
• Authors: Shen, Xing; Xiong, Guo-Lin; Jing, Yu; Xiao, He; Cui, Yu; Zhang, Yan-Feng; Shan, Ya-Jun; Xing, Shuang; Yang, Meng; Liu, Xiao-Lan; Dong, Bo; Wang, Li-Sheng; Luo, Qing-Liang; Yu, Zu-Yin; Cong, Yu-Wen
• Is Part Of: Cancer letters. Volume 356:Issue 2(2015)Part B
• Page Start: 686
• Page End: 696
• Publication Date: 2015-01-28
• Subjects: PKC protein kinase C -- AML acute myeloid leukemia -- PMA phorbol-12-myristate-13-acetate -- Ara-C cytosine arabinoside -- MAPK mitogen-activated protein kinase; Prostratin -- Differentiation -- AML -- Protein kinase C; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2014.10.018
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Prostratin inhibits the growth of acute myeloid leukemia (AML) cells by inducing differentiation. PKC-ERK-c-Myc signaling pathway plays a key role in the prostratin-mediated cell differentiation. Prostratin is shown to be able to potentiate cellular differentiation induced by chemotherapeutic agents such as Ara-C. Prostratin alone or administered with other anticancer agents may be effective in differentiation therapy of AML. 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.