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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Thymidylate synthase inhibition triggers glucose-dependent apoptosis in p53-negative leukemic cells

Cristina Muñoz-Pinedo1, Gema Robledo, Abelardo López-Rivas

  • 1Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, calle Ventanilla 11, 18001 Granada, Spain. cmunoz@liai.org

FEBS Letters
|July 15, 2004
PubMed

Insights

Chemotherapy drugs targeting DNA synthesis induce cell death. This study reveals that 5-fluoro-2-deoxyuridine (FUdR) triggers thymineless death in leukemia cells, independent of p53 and ROS, but dependent on glucose.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Chemotherapeutic agents inhibiting thymidine triphosphate synthesis induce apoptosis.
  • The precise mechanisms of this thymineless cell death remain largely unelucidated.
  • Understanding these pathways is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the mechanism of thymineless death induced by 5'-fluoro-2'-deoxyuridine (FUdR) in human myeloid leukemia U937 cells.
  • To determine the role of p53, reactive oxygen species (ROS), CD95, caspases, and glucose in FUdR-induced apoptosis.
  • To elucidate the mitochondrial involvement in this specific apoptotic pathway.

Main Methods:

  • Treatment of U937 leukemia cells with the thymidylate-synthase inhibitor FUdR.
  • Assessment of apoptosis markers, including caspase activation and mitochondrial integrity.
  • Investigation of the influence of p53, ROS, CD95, and glucose availability on the apoptotic process.

Main Results:

  • FUdR induced apoptosis in U937 cells, a process termed thymineless death.
  • This apoptosis was independent of p53, ROS generation, and CD95 activation.
  • Caspase activation occurred downstream of cytochrome c release but upstream of mitochondrial depolarization.
  • FUdR-induced apoptosis was contingent upon the presence of glucose, acting upstream of cytochrome c release.

Conclusions:

  • Thymidylate-synthase inhibition by FUdR triggers a distinct apoptotic pathway in leukemia cells.
  • Glucose metabolism plays a critical role in initiating this specific cell death cascade.
  • The findings offer insights into novel therapeutic strategies targeting leukemia cell survival.

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