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10-formyltetrahydrofolate dehydrogenase-induced c-Jun-NH2-kinase pathways diverge at the c-Jun-NH2-kinase substrate

Sampa Ghose1, Natalia V Oleinik, Natalia I Krupenko

  • 1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, USA.

Molecular Cancer Research : MCR
|January 17, 2009
PubMed

Insights

10-Formyltetrahydrofolate dehydrogenase (FDH) triggers apoptosis in cancer cells via JNK and ERK pathways. While JNK activation is crucial for FDH-induced cytotoxicity, its downstream targets like c-Jun or p53 are cell-type specific.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • 10-Formyltetrahydrofolate dehydrogenase (FDH) exhibits dual roles in cancer, suppressing proliferation via p53-dependent apoptosis but inducing cytotoxicity in p53-deficient cells.
  • Understanding the precise molecular mechanisms underlying FDH-induced cytotoxicity is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the signaling pathways involved in FDH-induced apoptosis in p53-deficient prostate cancer cells (PC-3).
  • To investigate the role of JNK and ERK pathways and their downstream targets in FDH-mediated cytotoxicity.
  • To compare the FDH-induced apoptotic mechanisms in p53-deficient and p53-proficient cancer cells.

Main Methods:

  • Utilized specific inhibitors (SP600125 for JNK, PD98059 for ERK) and siRNA knockdown to assess pathway involvement.
  • Employed dominant-negative mutants (TAM67) to investigate the role of c-Jun.
  • Performed pull-down assays to confirm direct protein-protein interactions.
  • Analyzed caspase activation (caspase 8 and 9) in different cell lines.

Main Results:

  • FDH induces apoptosis in PC-3 cells through simultaneous activation of JNK and ERK pathways.
  • JNK activation, leading to c-Jun phosphorylation, plays a more significant role than ERK in FDH-induced apoptosis in PC-3 cells.
  • In p53-proficient A549 cells, FDH activates JNK, but its downstream target is p53, not c-Jun.
  • FDH activates caspase 8 in PC-3 cells and caspase 9 in A549 cells.
  • High leucovorin supplementation inhibits FDH-induced JNK activation, suggesting a link between folate metabolism and MAPK pathways.

Conclusions:

  • JNK pathway activation is a conserved downstream mechanism of FDH-induced cytotoxicity across different cancer cell types.
  • The specific downstream targets of JNK (e.g., c-Jun, p53) and the activated caspase (caspase 8 or 9) are cell-type specific.
  • These findings highlight the intricate interplay between folate metabolism and MAPK signaling in cancer cell death.

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