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

Autor: Maksym Plachynta, Lei Xia, Fei Han, Yao Yao, Chen Yan, You-Jun Li, Jialei Song, Bin Deng, Jue Yang, Ye Wang, Mu Zhang, Tangjingjun Liu, Shu-Zhen Mu, Xiaogang Li, Eldad Zacksenhaus, Heng Luo, Gang Zhang, Yaacov Ben-David, Xiao Xiao, Xiao-Jiang Hao
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Oncotarget
ISSN: 1949-2553
Popis: // Tangjingjun Liu 1, 7, * , Yao Yao 1, 7, * , Gang Zhang 1 , Ye Wang 2 , Bin Deng 1 , Jialei Song 1, 8 , Xiaogang Li 1 , Fei Han 1 , Xiao Xiao 1, 7 , Jue Yang 1 , Lei Xia 1, 3 , You-Jun Li 4 , Maksym Plachynta 1 , Mu Zhang 1 , Chen Yan 1 , Shuzhen Mu 1, 7 , Heng Luo 1, 7 , Eldad Zacksenhaus 5, 6 , Xiaojiang Hao 1, 3, 7 , Yaacov Ben-David 1, 7 1 Department of Biology and Chemistry, The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guizhou, China 2 College of Ecology, Lishui University, Zhejiang, China 3 School of Pharmaceutical Sciences, Guizhou University, Guizhou, China 4 Department of Anatomy, Norman Bethune College of Medicine, Jilin University, Changchun, China 5 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 6 Division of Advanced Diagnostics, Toronto General Research Institute–University Health Network, Toronto, Ontario, Canada 7 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China 8 The 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.
Databáze: OpenAIRE
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