Abstract
Stabilization of G-quadruplex (G4) structures in promoters is a novel promising strategy to regulate gene expression at transcriptional and translational levels. c-KIT proto-oncogene encodes for a tyrosine kinase receptor. It is involved in several physiological processes, but it is also dysregulated in many diseases, including cancer. Two G-rich sequences able to fold into G4, have been identified in c-KIT proximal promoter, thus representing suitable targets for anticancer intervention. Herein, we screened an “in house” library of compounds for the recognition of these G4 elements and we identified three promising ligands. Their G4-binding properties were analyzed and related to their antiproliferative, transcriptional and post-transcriptional effects in MCF7 and HGC27 cell lines. Besides c-KIT, the transcriptional analysis covered a panel of oncogenes known to possess G4 in their promoters.From these studies, an anthraquinone derivative (AQ1) was found to efficiently downregulate c-KIT mRNA and protein in both cell lines. The targeted activity of AQ1 was confirmed using c-KIT–dependent cell lines that present either c-KIT mutations or promoter engineered (i.e., α155, HMC1.2 and ROSA cells).Present results indicate AQ1 as a promising compound for the target therapy of c-KIT-dependent tumors, worth of further and in depth molecular investigations.
Highlights
The c-KIT proto-oncogene (c-KIT) codes for a tyrosine kinase receptor (c-kit) that, once activated by stem cell factor (SCF) in mast cells, melanocytes and Cajal interstitial cells, participates in a broad range of physiological processes, including cell proliferation, migration, maturation and survival [1, 2].c-KIT is dysregulated in many diseases, including cancer [3]; in neoplastic diseases, its increased expression and auto-phosphorylation allows tumor cells to develop independently from growth and survival signals [4, 5]
All the members of our library were previously tested for their ability to stabilize the G4 structure of the human telomeric sequence as well as of a random DNA double helix, and a general preference for G4 vs dsDNA was observed for most of them [23,24,25,26,27,28,29]
naphthalene diimide (NDI) derivatives showed a preferential stabilization of the telomeric G4; they were not selected for further investigations
Summary
The c-KIT proto-oncogene (c-KIT) codes for a tyrosine kinase receptor (c-kit) that, once activated by stem cell factor (SCF) in mast cells, melanocytes and Cajal interstitial cells, participates in a broad range of physiological processes, including cell proliferation, migration, maturation and survival [1, 2]. Several small molecules that efficiently bind the G4 structures of c-KIT have been identified and most of them present an extended aromatic core that allows the stacking on the terminal G-tetrads [17,19] For some of these ligands the inhibition of c-KIT expression has been confirmed in cells: these include trisubstituted isoalloxazines, naphthalene diimide derivatives, substituted indenoisoquinolines and benzo[a] phenoxazines [12, 20,21,22]. Most of structural variations concern the compound side chains, either in terms of composition or relative localization on the pharmacophore This was a precise choice: upon stacking of the planar core, the side chains are available to achieve the selective recognition of G4 loops and grooves, which are the structural domains largely defining the unique conformational signature of G4s. Their effects on c-KIT mRNA and protein expression were evaluated in a panel of human cancer cell lines, including some well-known in vitro models of c-KIT-dependent tumors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
