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Cks overexpression enhances chemotherapeutic efficacy by overriding DNA damage checkpoints

Academic Article
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Overview

related to degree

  • Tat, John, Ph.D. in Molecular Medicine, Scripps Research 2011 - 2017

authors

  • del Rincon, S. V.
  • Widschwendter, M.
  • Sun, D.
  • Ekholm-Reed, S.
  • Tat, John
  • Teixeira, L. K.
  • Ellederova, Z.
  • Grolieres, E.
  • Reed, Steven
  • Spruck, C.

publication date

  • April 2015

journal

  • Oncogene  Journal

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.

subject areas

  • Animals
  • Antimetabolites, Antineoplastic
  • Apoptosis
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases
  • DNA Damage
  • DNA Replication
  • Disease Models, Animal
  • Female
  • Fluorouracil
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • S Phase Cell Cycle Checkpoints
  • Xenograft Model Antitumor Assays
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Identity

PubMed Central ID

  • PMC4245389

International Standard Serial Number (ISSN)

  • 0950-9232

Digital Object Identifier (DOI)

  • 10.1038/onc.2014.137

PubMed ID

  • 24858038
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Additional Document Info

start page

  • 1961

end page

  • 1967

volume

  • 34

issue

  • 15

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