Abstract
AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNAs, including those of genes required for cell growth and proliferation. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the stabilization of ARE-mRNA. The level of HuR in the cytoplasm is up-regulated in most cancer cells, resulting in the stabilization of ARE-mRNA. We developed the adenoviruses AdARET and AdAREF, which include the ARE of TNF-α and c-fos genes in the 3′-untranslated regions of the E1A gene, respectively. The expression of the E1A protein was higher in cancer cells than in normal cells, and virus production and cytolytic activities were also higher in many types of cancer cells. The inhibition of ARE-mRNA stabilization resulted in a reduction in viral replication, demonstrating that the stabilization system was required for production of the virus. The growth of human tumors that formed in nude mice was inhibited by an intratumoral injection of AdARET and AdAREF. These results indicate that these viruses have potential as oncolytic adenoviruses in the vast majority of cancers in which ARE-mRNA is stabilized.
Highlights
The use of conditionally replicative adenoviruses (CRAd) is an attractive tool for cancer therapy.Many types of CRAd have been developed to date, some of which are currently undergoing clinical trials [1]
Promoters of the telomerase gene [5] or prostate-specific antigen gene [6] are inserted into the 50 - untranslated region (UTR) of the E1A gene to produce CRAds that are activated in cancer cells
Since AU-rich elements (AREs)-containing mRNA is degraded under normal conditions, but is stabilized in cancer cells, viral E1A expression was expected to be higher in cancer cells than in normal cells
Summary
The use of conditionally replicative adenoviruses (CRAd) is an attractive tool for cancer therapy.Many types of CRAd have been developed to date, some of which are currently undergoing clinical trials [1]. The use of conditionally replicative adenoviruses (CRAd) is an attractive tool for cancer therapy. Two types of genetically engineered CRAd have been examined in detail [2]. Cancers 2020, 12, 1205 of viruses have mutations in the genes required for viral replication. The E1A or E1B55k gene deleted-virus [3,4] has been effective at killing pRB- or p53-deficient cancer cells. The other group consists of viruses that possess a cancer-specific transcription system in the virus genes required for replication, such as E1A. Promoters of the telomerase gene [5] or prostate-specific antigen gene [6] are inserted into the 50 - untranslated region (UTR) of the E1A gene to produce CRAds that are activated in cancer cells
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