No conflicts of interest were declared.
CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction †
Article first published online: 19 OCT 2011
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 226, Issue 3, pages 482–494, February 2012
How to Cite
Lee, A. J. X., Roylance, R., Sander, J., Gorman, P., Endesfelder, D., Kschischo, M., Jones, N. P., East, P., Nicke, B., Spassieva, S., Obeid, L. M., Birkbak, N. J., Szallasi, Z., McKnight, N. C., Rowan, A. J., Speirs, V., Hanby, A. M., Downward, J., Tooze, S. A. and Swanton, C. (2012), CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction . J. Pathol., 226: 482–494. doi: 10.1002/path.2998
- Issue published online: 16 JAN 2012
- Article first published online: 19 OCT 2011
- Accepted manuscript online: 26 SEP 2011 04:46AM EST
- Manuscript Accepted: 8 SEP 2011
- Manuscript Revised: 5 SEP 2011
- Manuscript Received: 24 JUL 2011
- drug resistance
Chromosomal instability (CIN) has been implicated in multidrug resistance and the silencing of the ceramide transporter, CERT, promotes sensitization to diverse cytotoxics. An improved understanding of mechanisms governing multidrug sensitization might provide insight into pathways contributing to the death of CIN cancer cells. Using an integrative functional genomics approach, we find that CERT-specific multidrug sensitization is associated with enhanced autophagosome–lysosome flux, resulting from the expression of LAMP2 following CERT silencing in colorectal and HER2+ breast cancer cell lines. Live cell microscopy analysis revealed that CERT depletion induces LAMP2-dependent death of polyploid cells following exit from mitosis in the presence of paclitaxel. We find that CERT is relatively over-expressed in HER2+ breast cancer and CERT protein expression acts as an independent prognostic variable and predictor of outcome in adjuvant chemotherapy-treated patients with primary breast cancer. These data suggest that the induction of LAMP2-dependent autophagic flux through CERT targeting may provide a rational approach to enhance multidrug sensitization and potentiate the death of polyploid cells following paclitaxel exposure to limit the acquisition of CIN and intra-tumour heterogeneity. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.