The role of autophagy in neoplastic cell response to oncolytic viruses
Botta, Ginevra (2009) The role of autophagy in neoplastic cell response to oncolytic viruses. [Tesi di dottorato] (Inedito)
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Oncolytic conditionally replicating adenoviruses (CRAds) are viral mutants able to selectively replicate in tumour cells. CRAds are considered a promising platform for cancer therapy. dl922-947, bearing a mutation in E1A gene and AdΔΔ, carrying mutations in both E1A and E1B genes, exhibited an antitumour effect against glioma and prostate cancer cells, respectively. Recently, it is thought that the adequate modulation of autophagy can enhance efficacy of anticancer therapy. However, the outcome of autophagy manipulation depends on the autophagy initiator, the combined stimuli, the extent of cellular damage and the type of cells. In this study, I characterized the role of autophagy in oncolytic adenovirus-induced therapeutics effects. When autophagy was inhibited at different steps by chloroquine (HCQ) or 3-methyladenine (3-MA), the cytotoxicity of dl922-947 and AdΔΔ in glioma and prostate cancer cells was augumented. These findings indicate that autophagy is a cell survival response in infected cells. Moreover, I showed that the oncolytic adenoviruses activated the Akt/mTOR/p70s6k pathway, that plays a central role in the negative regulation of autophagy, and, accordingly, inhibited the ERK pathway, that is a positive regulator of autophagy. Interestingly, a MEK inhibitor, PD98059, synergistically sensitized glioma cells to dl922-947 by increasing autophagy inhibition. These findings suggest that a disruption of ERK signalling pathway could greatly enhance the efficacy of CRAds by inhibiting autophagy. The observation that autophagy inhibitors increase adenoviruses antitumor activity in cancer cells suggests a novel multimodal strategy for virotherapy.
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