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Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance

Zhaoqing Wang1, Jing Xu, Jun-Ying Zhou

  • 1Program in Molecular Biology and Human Genetics, Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Cancer Research
|September 5, 2006
PubMed

Insights

Mitogen-activated protein kinase phosphatase-1 (MKP-1) confers cisplatin resistance by inactivating c-Jun NH2-terminal kinase (JNK). MKP-1 induction by cisplatin is crucial for cancer cell survival during chemotherapy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 negatively regulates MAPK signaling pathways.
  • MKP-1 is involved in cell survival under stress, including anticancer treatments, but its role in cisplatin resistance is unclear.

Purpose of the Study:

  • To investigate the role of MKP-1 in cisplatin resistance in human cancer cells.
  • To elucidate the signaling pathways regulated by MKP-1 during cisplatin treatment.

Main Methods:

  • Assessed MKP-1 induction by cisplatin in human cancer cell lines.
  • Utilized small interfering RNA (siRNA) to down-regulate MKP-1.
  • Employed MKP-1 knockout mouse embryonic fibroblasts (MEFs) to study cisplatin effects.
  • Analyzed the involvement of extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2-terminal kinase (JNK) signaling pathways.

Main Results:

  • Cisplatin induced MKP-1 transcriptionally via ERK signaling.
  • Overexpression of MKP-1 led to cisplatin resistance, while MKP-1 silencing sensitized cells to cisplatin.
  • MKP-1 knockout MEFs exhibited increased cisplatin-induced apoptosis, linked to JNK inactivation.
  • Inhibition of JNK, but not ERK or p38, blocked cisplatin-induced cell death.

Conclusions:

  • MKP-1 plays a critical role in conferring resistance to cisplatin chemotherapy.
  • JNK signaling is essential for cisplatin-induced apoptosis.
  • Targeting MKP-1 or modulating JNK activity may enhance cisplatin efficacy in cancer treatment.

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