Abstract
Overexpression of BMI1 correlates with cancer development, progression, and therapy failure; however, the underlying molecular mechanisms remain to be fully elucidated. Using the C666-1 nasopharyngeal cancer (NPC) model, the role of BMI1 in mediating response of NPC cells to radiation therapy (RT) was investigated. The results showed a novel radioresistance function for BMI1 in NPC, wherein BMI1 depletion sensitized NPC cells to RT. Cell cycle analysis and transmission electron microscopy (TEM) showed apoptosis as the major mode of cell death, and the mitochondria as a primary targeted cellular organelle. Genome-wide microarray and pathway analyses revealed that the P53 pathway is a critical mediator of this process. Cotransfection with siP53 rescued C666-1 cells from cytotoxicity upon BMI1 depletion and RT, thereby corroborating the role for P53. Pretreatment with the antioxidant, Trolox, inhibited apoptosis, indicating that production of reactive oxygen species (ROS) is also mediating cytotoxicity. In vivo, BMI1 depletion combined with RT abrogated tumor-forming capacity in SCID mice, showing the relevance of this process in a more complex tumor environment. Hence, we show a novel role for BMI1 in conferring radioresistance in cancer cells through the downregulation of p53-mediated apoptosis. These results suggest a potential strategy of BMI1 depletion combined with RT for tumors wherein BMI1 appears to be driving disease progression.
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Abbreviations
- NPC:
-
nasopharyngeal cancer
- RT:
-
radiation therapy
- TEM:
-
transmission electron microscopy
- PcG:
-
polycomb group
- ROS:
-
reactive oxygen species
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Acknowledgements
Dr. NM Alajez is a recipient of an Excellence in Radiation Research for the 21st Century (EIRR21) scholarship. This study was supported by a grant from the Canadian Institutes of Health Research (CIHR). We thank Kelly Stewart for assisting with the ROS experiments.
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Alajez, N., Shi, W., Hui, A. et al. Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy. Cell Death Differ 16, 1469–1479 (2009). https://doi.org/10.1038/cdd.2009.85
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DOI: https://doi.org/10.1038/cdd.2009.85
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