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Sci Rep. 2016 Nov 16;6:37213. doi: 10.1038/srep37213.

Intrinsic cellular signaling mechanisms determine the sensitivity of cancer cells to virus-induced apoptosis.

Author information

1
Department of Anatomy and Cell Biology, UF Health Cancer Center, UF Genetics Institute, University of Florida College of Medicine, Gainesville, Florida, USA.
2
Shaanxi Key Laboratory of Agriculture Molecular Biology, Department of Biochemistry and Molecular Biology, College of Life Science, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China.
3
Department of Urology, Qilu Hospital, Shandong University, Jinan, Shandong, China.

Abstract

Cancer cells of epithelial and mesenchymal phenotypes exhibit different sensitivities to apoptosis stimuli, but the mechanisms underlying this phenomenon remain partly understood. We constructed a novel recombinant adenovirus expressing Ad12 E1A (Ad-E1A12) that can strongly induce apoptosis. Ad-E1A12 infection of epithelial cancer cells displayed dramatic detachment and apoptosis, whereas cancer cells of mesenchymal phenotypes with metastatic propensity were markedly more resistant to this virus. Notably, forced detachment of epithelial cells did not further sensitize them to Ad-E1A12-induced apoptosis, suggesting that cell detachment is a consequence rather than the cause of Ad-E1A12-induced apoptosis. Ad-E1A12 increased phosphorylation of AKT1 and ribosomal protein S6 through independent mechanisms in different cell types. Ad-E1A12-induced AKT1 phosphorylation was PI3K-dependent in epithelial cancer cells, and mTOR-dependent in mesenchymal cancer cells. Epithelial cancer cells upon Ad-E1A12-induced detachment could not sustain AKT activation due to AKT1 degradation, but AKT1 activation was maintained in mesenchymal cancer cells. Expression of epithelial cell-restricted miR-200 family in mesenchymal cells limited mTOR signaling and sensitized them to Ad-E1A12-induced cell killing. Thus, epithelial cancer cells rely on the canonical PI3K-AKT signaling pathway for survival, while mesenchymal cancer cells deploy the PI3K-independent mTORC2-AKT axis in response to strong death stimuli.

PMID:
27849011
PMCID:
PMC5111159
DOI:
10.1038/srep37213
[Indexed for MEDLINE]
Free PMC Article

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