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

Alvin 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

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)482-94
Number of pages13
JournalThe Journal of pathology
Volume226
Issue number3
Early online date19 Oct 2011
DOIs
Publication statusPublished - Feb 2012

Bibliographical note

Acknowledgement
We thank the following: Sarah Mc Clelland, Jasmin Zohren and Rebecca Burrell for help with manuscript preparation; Hannah Armer and Lucy Collinson from the EM facility at Cancer Research UK (CR–UK) LRI and Niamh Murphy for help with the breast cancer TMA cohort. CS is funded by the Medical Research Council and CR–UK. AL, NM, AR, JD and ST are funded by CR–UK. ZS is funded by the National Institute of Health (Grant Nos NCI SPORE P50 CA89393 and R21LM008823-01A1), the Danish Council for Independent Research/Medical Sciences (FSS) and the Breast Cancer Research Foundation (BCRF).

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • Autophagy
  • Breast Neoplasms
  • Ceramides
  • Chromosomal Instability
  • Cisplatin
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression
  • Gene Silencing
  • Humans
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins
  • Middle Aged
  • Mitosis Modulators
  • Polyploidy
  • Protein-Serine-Threonine Kinases
  • RNA, Small Interfering
  • Receptor, ErbB-2
  • Tumor Cells, Cultured
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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