Journal article
CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid‐specific cancer cell death through autophagy induction
Cancer Research UK1
Queen Mary University of London2
Koblenz University of Applied Sciences3
University College London4
Medical University of South Carolina5
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark6
Department of Systems Biology, Technical University of Denmark7
University of Leeds8
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.
| Language: | English |
|---|---|
| Publisher: | John Wiley & Sons, Ltd. |
| Year: | 2012 |
| Pages: | 482-494 |
| ISSN: | 10969896 and 00223417 |
| Types: | Journal article |
| DOI: | 10.1002/path.2998 |
Adult Aged Aged, 80 and over Antineoplastic Agents Autophagy Breast Neoplasms CERT CERT1 protein, human Ceramides Chromosomal Instability Cisplatin Drug Resistance, Multiple Drug Resistance, Neoplasm Female Gene Expression Gene Silencing HER2 Humans LAMP2 LAMP2 protein, human Lysosomal Membrane Proteins Lysosomal-Associated Membrane Protein 2 Middle Aged Mitosis Modulators Polyploidy Protein Serine-Threonine Kinases RNA, Small Interfering Receptor, ErbB-2 Tumor Cells, Cultured autophagy drug resistance polyploidy
