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.
Highlights
Transcription factors (TFs) are frequently modulated during cancer initiation and progression [1, 2]
The identified compounds are structurally related to diterpene family of small molecules, which are known agonists of protein kinase C (PKC). These PKC agonists (PKCAs) induced PKC phosphorylation leading to activation of the mitogen-activated protein kinase (MAPK) pathway, increased cell attachment and erythroid to megakaryocytic conversion (EMC), whereas pharmacological inhibition of PKC or MAPK diminished the effect of our PKCAs
As the majority of splenic cells represent erythroleukemia in these mice, the results suggest that over-activation of Friend Leukemia virus integration-1 (Fli-1) or activation of the PKC-MAPKFli-1 axis by A75 suppress leukemogenesis at least in part by inducing erythroid to megakaryocytic differentiation (EMD)
Summary
Transcription factors (TFs) are frequently modulated during cancer initiation and progression [1, 2]. The Friend Leukemia virus integration-1 (Fli-1), a member of ETS gene family, is activated by retroviral insertional mutagenesis in F-MuLVinduced erythroleukemias [3, 4] This TF undergoes translocation in most human Ewing sarcomas, generating an EWS-Fli-1 fusion protein with potent oncogenic activity [5]. Fli-1 affects various human autoimmune diseases including Systemic Lupus Erythematosus (SLE) and Systemic sclerosis/scleroderma [14,15,16,17,18]. Based on these diverse biological properties, Fli-1 may be an excellent therapeutic target for various diseases and cancers that are driven by high levels of this ETS factor
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
