Abstract
Caspase-8 is frequently deficient in several kinds of human tumors, suggesting that certain effects of this enzyme restrict tumor development. To examine the nature of the cellular function whose regulation by caspase-8 contributes to its antitumor effect, we assessed the impact of caspase-8 deficiency on cell transformation in vitro. Caspase-8-deficient mouse embryonic fibroblasts immortalized with the SV40 T antigen did not survive when cultured in soft agar, and were nontumorogenic in nude mice. However, the rate of transformation of these cells during their continuous growth in culture, as reflected in the observed emergence of cells that do grow in soft agar and are able to form tumors in nude mice, was far higher than that of cells expressing caspase-8. These findings indicate that caspase-8 deficiency can contribute to cancer development in a way that does not depend on the enzyme's participation in killing of the tumor cells by host immune cytotoxic mechanisms, or on its involvement in the cell-death process triggered upon detachment of the cells from their substrate, but rather concerns cell-autonomous mechanisms that affect the rate of cell transformation.
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Abbreviations
- CHI:
-
cycloheximide
- DMEM:
-
Dulbecco's modified Eagle's minimal essential medium
- FCS:
-
fetal calf serum
- DMEM–FCS:
-
DMEM supplemented with 10% FCS
- KO:
-
knockout
- MEF:
-
mouse embryonic fibroblasts
- PBS:
-
phosphate-buffered saline
- WT:
-
wild type
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Acknowledgements
We thank Dr. Raya Eilam-Altstadter for help in quantifying the growth of colonies in soft agar, and Inna Kolesnik and Tatiana Shalevich for genotyping the mice. This study was supported in part by grants from Ares Trading SA, Switzerland; a Center of Excellence Grant from the Flight Attendant Medical Research Institute (FAMRI); and the Kekst Family Center for Medical Genetics at The Weizmann Institute of Science.
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Krelin, Y., Zhang, L., Kang, TB. et al. Caspase-8 deficiency facilitates cellular transformation in vitro. Cell Death Differ 15, 1350–1355 (2008). https://doi.org/10.1038/cdd.2008.88
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DOI: https://doi.org/10.1038/cdd.2008.88
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