title: The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase.
abstract: CDT2/L2DTL/RAMP is one of the substrate receptors of the Cullin Ring Ubiquitin Ligase 4 that targets for ubiquitin mediated degradation a number of substrates, such as CDT1, p21 and CHK1, involved in the regulation of cell cycle and survival. Here we show that CDT2 depletion was alone able to induce the apoptotic death in 12/12 human cancer cell lines from different tissues, regardless of the mutation profile and CDT2 expression level. Cell death was associated to rereplication and to loss of CDT1 degradation. Conversely, CDT2 depletion did not affect non-transformed human cells, such as immortalized kidney, lung and breast cell lines, and primary cultures of endothelial cells and osteoblasts. The ectopic over-expression of an activated oncogene, such as the mutation-activated RAS or the amplified MET in non-transformed immortalized breast cell lines and primary human osteoblasts, respectively, made cells transformed in vitro, tumorigenic in vivo, and susceptible to CDT2 loss. The widespread effect of CDT2 depletion in different cancer cells suggests that CDT2 is not in a synthetic lethal interaction to a single specific pathway. CDT2 likely is a non-oncogene to which transformed cells become addicted because of their enhanced cellular stress, such as replicative stress and DNA damage.
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Olivero
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy; present address: HUGEF, Human Genetics Foundation, Torino, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dettori
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy; present address: Signal Transduction Laboratory, Cancer Research UK London Research Institute, London U.K.
authors.forename: Davide
authors.initials: D
authors.lastname: Zecchin
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy; present address: Washington University in St. Louis, St. Louis, MO.
authors.forename: Erica
authors.initials: E
authors.lastname: Lantelme
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy.
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
mesh_terms: D045744:Cell Line, Tumor; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; C429530:DTL protein, human; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases