title: Cks overexpression enhances chemotherapeutic efficacy by overriding DNA damage checkpoints.
abstract: Cdc kinase subunit (Cks) proteins Cks1 and Cks2 are adaptor-like proteins that bind many cyclin-dependent kinases. A wealth of clinical data has shown that Cks proteins are overexpressed in many types of human cancers and this often correlates with increased tumor aggressiveness. Previously, we showed that Cks overexpression abrogates the intra-S-phase checkpoint, a major barrier to oncogene-mediated transformation. Interestingly, the intra-S-phase checkpoint is crucial for the cellular response to replication stress, a major pathway of apoptosis induction by many chemotherapeutic agents. Here, we demonstrate cancer cells that overexpress Cks1 or Cks2 override the intra-S-phase checkpoint in the presence of replication stress-inducing chemotherapies such as 5-Fluorouracil (5-FU) and methotrexate (MTX) leading to enhanced sensitivity in vitro and in vivo. Furthermore, enforced expression of Cks1 in an MTX-resistant breast cancer cell line was found to restore drug sensitivity. Our results suggest that Cks proteins are important determinants of apoptosis induction of replication stress-inducing chemotherapies such as 5-FU.
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: del Rincón
authors.affiliation: Department of Gynaecological Oncology, University College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Widschwendter
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ekholm-Reed
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tat
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: Teixeira
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ellederova
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Grolieres
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Reed
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Spruck
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis* / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D018844:Cyclin-Dependent Kinases; D005472:Fluorouracil