The engineered oncolytic adenovirus ONYX-015 inactivates p53 by altering RNA export pathways, thus revealing a potentially interesting therapeutic target.
Several viruses have been engineered with the capacity to replicate in and exclusively kill cancer cells, although the precise molecular mechanism behind the selectivity of these oncolytic viruses has not always been clear. While studying the oncolytic adenovirus ONYX-015, O'Shea and colleagues have found that tumour cells have alterations in RNA export pathways, revealing a previously unidentified and therapeutically interesting target that governs the selectivity of this virus.
Cells seem to have evolved a defence mechanism to deal with virus infection — stabilization and activation of the tumour suppressor p53 can provoke the premature apoptosis of the infected cell, limiting both viral replication and spread. Therefore, many viruses have evolved mechanisms to subvert the host p53 response. Given that the p53 pathway is mutated in a wide range of cancers, ONYX-015 was designed to specifically replicate in tumour cells that lacked a functional p53 pathway — the E1B-55K viral gene product that targets the tumour suppressor p53 for degradation is deleted in this virus. Surprisingly though, ONYX-015 has efficacy in tumour cells irrespective of their p53 status, prompting O'Shea and colleagues to investigate further.
Initially the authors looked at ONYX-015 infection in normal primary human epithelial lines with a wild-type p53 pathway. As expected, ONYX-015 was unable to successfully replicate and p53 was stabilized in the nucleus. Surprisingly though, this stabilized form of p53 was not active and did not induce apoptosis, indicating that viral products other than E1B-55K can restrict p53 activation. So, the authors next addressed the p53-independent functions of E1B-55K, which include the shutdown of host protein synthesis allowing late viral protein production. By using a set of adenoviruses that were deficient in specific functions of E1B-55K, the authors found that ONYX-015 was unable to induce late viral protein production due to a defect in late viral RNA export from the nucleus. But why should this be different in cancer cells? All the tumour cells that support the full lytic viral replication of ONYX-015 compensated for the defect in late viral RNA export, showing that normal and tumour cells differ markedly in this respect.
These data provide not only a further opportunity to understand how p53 can be inactivated, but also indicate a need to investigate whether the export of late viral RNA shares some characteristics with the export of RNAs important in growth control and tumorigenesis.
Nicola McCarthy
References
O'Shea et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell6, 611–623 (2004) | Article | PubMed |
