Chemovirotherapeutic Treatment Using Camptothecin Enhances Oncolytic Measles Virus-Mediated Killing of Breast Cancer Cells.
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ABSTRACT:
SUBMITTER: Tai CJ
PROVIDER: S-EPMC6494908 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Project description:Measles viruses derived from the live-attenuated Edmonton-B vaccine lineage are currently investigated as novel anti-cancer therapeutics. In this context, tumor specificity and oncolytic potency are key determinants of the therapeutic index. Here, we describe a systematic and comprehensive analysis of a recently developed post-entry targeting strategy based on the incorporation of microRNA target sites (miRTS) into the measles virus genome. We have established viruses with target sites for different microRNA species in the 3' untranslated regions of either the N, F, H, or L genes and generated viruses harboring microRNA target sites in multiple genes. We report critical importance of target-site positioning with proximal genomic positions effecting maximum vector control. No relevant additional effect of six versus three miRTS copies for the same microRNA species in terms of regulatory efficiency was observed. Moreover, we demonstrate that, depending on the microRNA species, viral mRNAs containing microRNA target sites are directly cleaved and/or translationally repressed in presence of cognate microRNAs. In conclusion, we report highly efficient control of measles virus replication with various miRTS positions for development of safe and efficient cancer virotherapy and provide insights into the mechanisms underlying microRNA-mediated vector control.
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Project description:Measles is a highly transmissible disease caused by measles virus and remains a major cause of child mortality in developing countries. Measles virus nucleoprotein (N) encapsidates the RNA genome of the virus for providing protection from host cell endonucleases and for specific recognition of viral RNA as template for transcription and replication. This protein is over-expressed at the time of viral replication. The C-terminal of N protein is intrinsically disordered, which enables this protein to interact with several host cell proteins. It was previously proved in our laboratory that N expressing human cancerous cells undergo programmed cell death because of reactive oxygen species (ROS) generation as well as Caspase 3 activation. The phosphoprotein (P) along with N protein enclosed viral genomic RNA forming a ribonucleoprotein complex (RNP). It also establishes interaction with the large protein (L) i.e. viral RNA dependent RNA polymerase to ensure viral replication within host cells. The host cell receptors of this virus are CD46, SLAM/CD150 and PVRL4. Measles virus is latently oncotropic in nature and possesses oncolytic property by syncytia formation. We try to highlight the application of this property in developing a virotherapeutic vehicle.
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