Oncotarget

Research Papers:

A screen for Fli-1 transcriptional modulators identifies PKC agonists that induce erythroid to megakaryocytic differentiation and suppress leukemogenesis

Tangjingjun Liu, Yao Yao, Gang Zhang, Ye Wang, Bin Deng, Jialei Song, Xiaogang Li, Fei Han, Xiao Xiao, Jue Yang, Lei Xia, You-Jun Li, Maksym Plachynta, Mu Zhang, Chen Yan, Shuzhen Mu, Heng Luo, Eldad Zacksenhaus, Xiaojiang Hao and Yaacov Ben-David _

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Oncotarget. 2017; 8:16728-16743. https://doi.org/10.18632/oncotarget.14377

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Abstract

Tangjingjun Liu1,7,*, Yao Yao1,7,*, Gang Zhang1, Ye Wang2, Bin Deng1, Jialei Song1,8, Xiaogang Li1, Fei Han1, Xiao Xiao1,7, Jue Yang1, Lei Xia1,3, You-Jun Li4, Maksym Plachynta1, Mu Zhang1, Chen Yan1, Shuzhen Mu1,7, Heng Luo1,7, Eldad Zacksenhaus5,6, Xiaojiang Hao1,3,7, Yaacov Ben-David1,7

1Department of Biology and Chemistry, The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guizhou, China

2College of Ecology, Lishui University, Zhejiang, China

3School of Pharmaceutical Sciences, Guizhou University, Guizhou, China

4Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, China

5Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

6Division of Advanced Diagnostics, Toronto General Research Institute–University Health Network, Toronto, Ontario, Canada

7State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China

8The Laboratory of Cell Biochemistry and Topogenic Regulation, College of Bioengineering and Faculty of Sciences, Chongqing University, Chongqing, China

*These authors have contributed equally to this work

Correspondence to:

Yaacov Ben-David, email: yaacovbendavid@hotmail.com

Xiaojiang Hao, email: haoxj@mail.kib.ac.cn

Keywords: Fli-1, PKC, erythroid and megakaryocytic differentiation, leukemia therapy, drug screens

Received: June 20, 2016    Accepted: December 07, 2016    Published: December 30, 2016

ABSTRACT

The ETS-related transcription factor Fli-1 affects many developmental programs including erythroid and megakaryocytic differentiation, and is frequently de-regulated in cancer. Fli-1 was initially isolated following retrovirus insertional mutagenesis screens for leukemic initiator genes, and accordingly, inhibition of this transcription factor can suppress leukemia through induction of erythroid differentiation. To search for modulators of Fli-1, we hereby performed repurposing drug screens with compounds isolated from Chinese medicinal plants. We identified agents that can transcriptionally activate or inhibit a Fli-1 reporter. Remarkably, agents that increased Fli-1 transcriptional activity conferred a strong anti-cancer activity upon Fli-1-expressing leukemic cells in culture. As opposed to drugs that suppress Fli1 activity and lead to erythroid differentiation, growth suppression by these new Fli-1 transactivating compounds involved erythroid to megakaryocytic conversion (EMC). The identified compounds are structurally related to diterpene family of small molecules, which are known agonists of protein kinase C (PKC). In accordance, these PKC agonists (PKCAs) induced PKC phosphorylation leading to activation of the mitogen-activated protein kinase (MAPK) pathway, increased cell attachment and EMC, whereas pharmacological inhibition of PKC or MAPK diminished the effect of our PKCAs. Moreover, in a mouse model of leukemia initiated by Fli-1 activation, the PKCA compounds exhibited strong anti-cancer activity, which was accompanied by increased presence of CD41/CD61 positive megakaryocytic cells in leukemic spleens. Thus, PKC agonists offer a novel approach to combat Fli-1-induced leukemia, and possibly other cancers,by inducing EMC in part through over-activation of the PKC-MAPK-Fli-1 pathway.


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