Autophagy is an evolutionarily conserved process regulating cellular homeostasis via digestion of dysfunctional proteins and whole cellular organelles by mechanisms, involving their enclosure into double-membrane vacuoles that are subsequently fused to lysosomes. Glioma stem cells utilize autophagy as a main mechanism of cell survival and stress response. Most recently, we and others demonstrated induction of autophagy in gliomas in response to treatment with chemical drugs, such as temozolomide (TMZ) or oncolytic adenoviruses (Ads). As autophagy has been implicated in the mechanism of Ad-mediated cell killing, autophagy deficiency in some glioma tumors could be the reason for their resistance to oncolysis. Despite the observed connection, the exact relationship between autophagy-activating cell signaling and adenoviral infection remains unclear. Here, we report that inhibition of autophagy in target glioma cells induces their resistance to killing by oncolytic agent CRAd-S-5/3. Furthermore, we found that downregulation of autophagy inducer Beclin-1 inhibits replication-competent Ad-induced oncolysis of human glioma by suppressing cell proliferation and inducing premature senescence. To overcome the autophagy-deficient state of such glioma cells and restore their susceptibility to oncolytic Ad infection, we propose treating glioma tumors with an anticancer drug tamoxifen (TAM) as a means to induce apoptosis in Ad-targeted cancer cells via upregulation of BAX/PUMA genes. In agreement with the above hypothesis, our data suggest that TAM improves susceptibility of Beclin-1-deficient glioma cells to CRAd-S-5/3 oncolysis by means of activating autophagy and pro-apoptotic signaling pathways in the target cancer cells.
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This research was supported by Russian Fund of Fundamental Research (number 11 411.0008700. 13.082 and number 13 411. 1008799.13.120 Russia, MAB) and private donors. We are grateful to Dr. Cobbs for providing patient-derived tumor cells and to Dr. Cobbs’s laboratory personnel for their support and technical assistance with experiments.
NVK, MAB, JM, and IVU performed the experiments. AVB, ZGK, AIK, AK, DO, TX, MSL, and IVU analyzed the data and wrote/edited the manuscript. AK and IVU assessed IHC score. TX performed statistical evaluation. MAB, AVB, and IVU designed the experiments, analyzed and interpreted the data, and proofread the manuscript.
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The authors declare that they have no conflict of interest.
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Kaverina, N.V., Kadagidze, Z.G., Borovjagin, A.V. et al. Tamoxifen overrides autophagy inhibition in Beclin-1-deficient glioma cells and their resistance to adenovirus-mediated oncolysis via upregulation of PUMA and BAX. Oncogene 37, 6069–6082 (2018). https://doi.org/10.1038/s41388-018-0395-9
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