title: 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.
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Alvin J X
authors.initials: AJ
authors.lastname: Lee
authors.forename: Rebecca
authors.initials: R
authors.lastname: Roylance
authors.forename: Jil
authors.initials: J
authors.lastname: Sander
authors.forename: Patricia
authors.initials: P
authors.lastname: Gorman
authors.forename: David
authors.initials: D
authors.lastname: Endesfelder
authors.forename: Maik
authors.initials: M
authors.lastname: Kschischo
authors.forename: Neil P
authors.initials: NP
authors.lastname: Jones
authors.forename: Philip
authors.initials: P
authors.lastname: East
authors.forename: Barbara
authors.initials: B
authors.lastname: Nicke
authors.forename: Stefka
authors.initials: S
authors.lastname: Spassieva
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Nicolai Juul
authors.initials: NJ
authors.lastname: Birkbak
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.forename: Nicole C
authors.initials: NC
authors.lastname: McKnight
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rowan
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hanby
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Tooze
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology; D043171:Chromosomal Instability / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000378:metabolism / Q000502:physiology; D008875:Middle Aged; D050258:Mitosis Modulators / Q000494:pharmacology; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D002945:Cisplatin; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D050258:Mitosis Modulators; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C497811:LAMP2 protein, human; C119090:CERT1 protein, human