CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction

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 t...

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Published in:The Journal of pathology 2012-02, Vol.226 (3), p.482-494
Main Authors: Lee, Alvin J. X., Roylance, Rebecca, Sander, Jil, Gorman, Patricia, Endesfelder, David, Kschischo, Maik, Jones, Neil P., East, Philip, Nicke, Barbara, Spassieva, Stefka, Obeid, Lina M., Birkbak, Nicolai Juul, Szallasi, Zoltan, McKnight, Nicole C., Rowan, Andrew J., Speirs, Valerie, Hanby, Andrew M., Downward, Julian, Tooze, Sharon A., Swanton, Charles
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic Agents - pharmacology
autophagy
Autophagy - drug effects
Autophagy - physiology
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Ceramides - metabolism
Ceramides - pharmacology
CERT
Chromosomal Instability - physiology
Cisplatin - pharmacology
drug resistance
Drug Resistance, Multiple - genetics
Drug Resistance, Multiple - physiology
Drug Resistance, Neoplasm - genetics
Drug Resistance, Neoplasm - physiology
Female
Gene Expression
Gene Silencing - physiology
HER2
Humans
Investigative techniques, diagnostic techniques (general aspects)
LAMP2
Lysosomal Membrane Proteins - metabolism
Lysosomal Membrane Proteins - physiology
Lysosomal-Associated Membrane Protein 2
Medical sciences
Middle Aged
Mitosis Modulators - pharmacology
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Polyploidy
Protein Serine-Threonine Kinases - antagonists & inhibitors
Protein Serine-Threonine Kinases - deficiency
Receptor, ErbB-2
RNA, Small Interfering - pharmacology
Tumor Cells, Cultured
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Summary: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.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.2998