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 journalArticle

30 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

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Chromosomal Instability
Polyploidy
Autophagy
Cell Death
Breast Neoplasms
Paclitaxel
Drug Therapy
Neoplasms
Ceramides
Multiple Drug Resistance
Adjuvant Chemotherapy
Genomics
Lysosomes
Mitosis
Microscopy
Cell Line
Proteins

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

Cite this

Lee, A. J. X., Roylance, R., Sander, J., Gorman, P., Endesfelder, D., Kschischo, M., ... Swanton, C. (2012). CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction. The Journal of pathology, 226(3), 482-94. https://doi.org/10.1002/path.2998

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

In: The Journal of pathology, Vol. 226, No. 3, 02.2012, p. 482-94.

Research output: Contribution to journalArticle

Lee, AJX, Roylance, R, Sander, J, Gorman, P, Endesfelder, D, Kschischo, M, Jones, NP, East, P, Nicke, B, Spassieva, S, Obeid, LM, Birkbak, NJ, Szallasi, Z, McKnight, NC, Rowan, AJ, Speirs, V, Hanby, AM, Downward, J, Tooze, SA & Swanton, C 2012, 'CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction', The Journal of pathology, vol. 226, no. 3, pp. 482-94. https://doi.org/10.1002/path.2998
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. / CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction. In: The Journal of pathology. 2012 ; Vol. 226, No. 3. pp. 482-94.
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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.",
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T1 - CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction

AU - Lee, Alvin J X

AU - Roylance, Rebecca

AU - Sander, Jil

AU - Gorman, Patricia

AU - Endesfelder, David

AU - Kschischo, Maik

AU - Jones, Neil P

AU - East, Philip

AU - Nicke, Barbara

AU - Spassieva, Stefka

AU - Obeid, Lina M

AU - Birkbak, Nicolai Juul

AU - Szallasi, Zoltan

AU - McKnight, Nicole C

AU - Rowan, Andrew J

AU - Speirs, Valerie

AU - Hanby, Andrew M

AU - Downward, Julian

AU - Tooze, Sharon A

AU - Swanton, Charles

N1 - 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).

PY - 2012/2

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N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents

KW - Autophagy

KW - Breast Neoplasms

KW - Ceramides

KW - Chromosomal Instability

KW - Cisplatin

KW - Drug Resistance, Multiple

KW - Drug Resistance, Neoplasm

KW - Female

KW - Gene Expression

KW - Gene Silencing

KW - Humans

KW - Lysosomal-Associated Membrane Protein 2

KW - Lysosome-Associated Membrane Glycoproteins

KW - Middle Aged

KW - Mitosis Modulators

KW - Polyploidy

KW - Protein-Serine-Threonine Kinases

KW - RNA, Small Interfering

KW - Receptor, ErbB-2

KW - Tumor Cells, Cultured

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/path.2998

DO - 10.1002/path.2998

M3 - Article

C2 - 21953249

VL - 226

SP - 482

EP - 494

JO - The Journal of pathology

JF - The Journal of pathology

SN - 0022-3417

IS - 3

ER -