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Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival

Larry M Karnitz1, Karen S Flatten, Jill M Wagner

  • 1Division of Oncology Research, Guggenheim 13, Mayo Clinic College of Medicine, 200 First Street, S.W., Rochester, Minnesota 55905, USA. Karnitz.Larry@Mayo.edu

Molecular Pharmacology
|August 30, 2005
PubMed

Insights

Gemcitabine and cytarabine activate DNA damage response pathways. Both pathways are crucial for tumor cell survival after gemcitabine treatment, with ATM playing a differential role depending on the agent.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • DNA-damaging antineoplastic therapies activate distinct signaling pathways.
  • These pathways involve kinases like ATM, ATR, Chk1, and Chk2, and complexes such as Rad9-Hus1-Rad1.
  • Gemcitabine and cytarabine are chemotherapeutics that disrupt DNA replication.

Purpose of the Study:

  • To investigate the roles of DNA damage signaling pathways in tumor cell survival following gemcitabine and cytarabine treatment.
  • To determine how ATM, ATR, Chk1, and Rad9 contribute to cellular responses to these chemotherapeutic agents.

Main Methods:

  • Utilized cell lines deficient in key DNA damage response proteins (Rad9, Chk1, ATR, ATM).
  • Assessed sensitivity to gemcitabine and cytarabine in these deficient cell lines.
  • Evaluated the impact of ATM depletion on sensitivity to gemcitabine, cytarabine, and ionizing radiation.

Main Results:

  • Cells lacking Rad9, Chk1, or ATR exhibited increased sensitivity to both gemcitabine and cytarabine, independent of p53.
  • ATM depletion sensitized cells to gemcitabine and ionizing radiation, but not to cytarabine.
  • Gemcitabine treatment activated both ATM/Chk2 and ATR/Chk1 signaling pathways.

Conclusions:

  • Gemcitabine triggers both major DNA damage checkpoint signaling pathways.
  • Both pathways are essential for tumor cell survival after gemcitabine-induced replication stress.
  • ATM plays a differential role in cell survival depending on whether cells are treated with gemcitabine or cytarabine, despite both agents stalling replication forks.

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