Productive viral infection mimics oncogenic transformation of different things, and some of the same molecular mechanisms used by viruses and cancer cells to disrupt key homeostatic mechanism. This analogy forms the basis for the development of oncolytic viruses”” that are designed to specifically target and destroy cancer cells. Although some selection strategies involve engineering viruses so that they specifically bind to cancer, a more interesting approach involves the development of a virus that only cancer cells contain specific defects mimic homeostatic control. For example, one of the products of the adenovirus E1B locus is a protein that specifically interfere with the function of p53, and thus weakening the host antiviral response is dependent on human p53 resulted in inhibition of DNA synthesis and / or apoptosis. Mutant forms of adenovirus E1B 55K imitate not be limited to cells with defective p53 function, ie cancer. Some groups developed adenovirus E1B mutants for cancer therapy, and promising results have been obtained with some of them, including Onyx Pharmaceuticals’. Another promising approach to take advantage of the presence of active Ras mutant
Rhabdovirus Virus RNA are also being developed as an oncolytic agent. His tumor selectivity is mainly related to the fact that the tumor cells are often resistant to the antiviral effects of type I interferons (IFN), which can completely suppress viral replication in normal cells. Removing mechanisms to suppress virus production improved oncolytic autocrine IFN activity while further reducing the toxicity to normal cells of the host. Researchers designed RNAi screen to identify synthetic lethal cytoprotective pathways that limit the destruction of tumor cells induced by the Maraba rhabdovirus in three human cancer cell lines are different. ”” They hit enriched gene function in two of the three main ways that respond to endoplasmic reticular (ER), often referred to as the unfolded protein response (UPR). More specifically, the display and IRE1/XBP1 ATF6 involved in pathways and downstream genes involved in the transport of proteins from the ER to the aggregate of the proteasome, for cytoprotection. Importantly, this group also identified a novel small molecule inhibitor of IRE1 that also sensitized tumor but not normal cells against the effects of oncolytic virus in vitro and in xenografts.
Therefore, if the inhibitor can be further optimized to increase its potential, there is a good chance you could translate preclinical observations in cancer patients. At first glance it may seem surprising that PERK/eIF2a pulled the arm of the UPR is not identified, but it makes sense. EIF2a phosphorylation results in global down-regulation of the cap-dependent translation host, so that viruses that grow different mechanisms preventing eIF2a phosphorylation or downstream effects on normal cells. In addition, we have observed that many tumor cells show an increase in eIF2a phosphorylation or translational arrest in response to ER stress and proteotoxic, so that this arm of the UPR can still disable a subset of cancer. Cancer link between the proteasome and autophagy is impaired, which may also be useful for productive viral infection if autophagy plays in limiting the somerole. It can also predict that knockdown of UPR or degeneration ER-associated (ERAD) component will cause the accumulation of protein aggregates in the ER and subsequent viral infection dramatically worsen the situation, focusing on the ER-Golgi network excessive increase in synthetic protein loading.
In fact, inhibition of ER stress and UPR because characteristics of the infected cells, but not resolved rapidly and cause a marked increase in the accumulation of protein aggregates, indicating that severe sensitization caused by pretreatment with inhibitors UPR has not been caused by this mechanism. In contrast, inhibition of the UPR prerequisite appears cells”” cell death induced by upregulating the expression of caspase adapter protein virus Next, RAIDD, and promoting the activation of caspase-2 , and caspase-2 knockdown recover almost completely synthetic lethal interactions between inhibition of the UPR and viral infections. Recent work by Green Doug group demonstrated that activation mediated RAIDD caspase-2 is controlled by the transcription factor stress response, the HSF-1, suggesting that the protein heatshocked and / or other molecular chaperones ( perhaps based on ER?) may play a central role in controlling stressinduced activation of caspase-2.