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Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription

Carly St Germain1, Nima Niknejad, Laurie Ma

  • 1Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Neoplasia (New York, N.Y.)
|July 24, 2010
PubMed

Insights

Activating transcription factor 3 (ATF3) mediates cisplatin

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cisplatin is a vital chemotherapeutic agent with largely undefined mechanisms of action.
  • Understanding cisplatin's cytotoxicity is crucial for enhancing its therapeutic efficacy.
  • Activating transcription factor 3 (ATF3) is a potential mediator of stress responses.

Purpose of the Study:

  • To investigate the role of ATF3 in cisplatin-induced cytotoxicity.
  • To elucidate the signaling pathways involved in ATF3 induction by cisplatin.

Main Methods:

  • Assessed ATF3 expression in five tumor cell lines following cisplatin and carboplatin treatment.
  • Utilized MAPK pathway inhibitors (JNK, ERK, p38) to study ATF3 induction.
  • Employed small hairpin RNA (shRNA) to target ATF3 in lung carcinoma cells.
  • Compared cisplatin sensitivity in ATF3-/- and ATF3+/+ murine embryonic fibroblasts (MEFs).

Main Results:

  • Cisplatin and carboplatin consistently induced ATF3 expression independently of p53, BRCA1, and ISR.
  • ATF3 induction by cisplatin is dependent on the mitogen-activated protein kinase (MAPK) pathway.
  • Inhibition of MAPK pathways decreased ATF3 induction and cisplatin's cytotoxic effects.
  • Targeting ATF3 or using ATF3-deficient cells attenuated cisplatin's cytotoxicity.

Conclusions:

  • Cisplatin induces ATF3 expression via a p53, BRCA1, and ISR-independent, MAPK-dependent mechanism.
  • ATF3 plays a significant role in mediating cisplatin's cytotoxic effects.
  • Targeting ATF3 may represent a strategy to enhance cisplatin chemotherapy efficacy.

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