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

Abstract
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.
AuthorsAlvin J X Lee, Rebecca Roylance, Jil Sander, Patricia Gorman, David Endesfelder, Maik Kschischo, Neil P Jones, Philip East, Barbara Nicke, Stefka Spassieva, Lina M Obeid, Nicolai Juul Birkbak, Zoltan Szallasi, Nicole C McKnight, Andrew J Rowan, Valerie Speirs, Andrew M Hanby, Julian Downward, Sharon A Tooze, Charles Swanton
JournalThe Journal of pathology (J Pathol) Vol. 226 Issue 3 Pg. 482-94 (Feb 2012) ISSN: 1096-9896 [Electronic] England
PMID21953249 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Chemical References
  • Antineoplastic Agents
  • Ceramides
  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins
  • Mitosis Modulators
  • RNA, Small Interfering
  • CERT1 protein, human
  • Receptor, ErbB-2
  • Protein Serine-Threonine Kinases
  • Cisplatin
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents (pharmacology)
  • Autophagy (drug effects, physiology)
  • Breast Neoplasms (drug therapy, genetics)
  • Ceramides (metabolism, pharmacology)
  • Chromosomal Instability (physiology)
  • Cisplatin (pharmacology)
  • Drug Resistance, Multiple (genetics, physiology)
  • Drug Resistance, Neoplasm (genetics, physiology)
  • Female
  • Gene Expression
  • Gene Silencing (physiology)
  • Humans
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins (metabolism, physiology)
  • Middle Aged
  • Mitosis Modulators (pharmacology)
  • Polyploidy
  • Protein Serine-Threonine Kinases (antagonists & inhibitors, deficiency)
  • RNA, Small Interfering (pharmacology)
  • Receptor, ErbB-2
  • Tumor Cells, Cultured

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