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MKP-1 suppresses PARP-1 degradation to mediate cisplatin resistance

J Wang1,2, D H Kho1,2, J-Y Zhou1,2

  • 1Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI, USA.

Oncogene
|June 27, 2017
PubMed

Insights

Mitogen-activated protein kinase phosphatase-1 (MKP-1) promotes cisplatin resistance by maintaining poly(ADP-ribose) polymerase-1 (PARP-1) levels. Inhibiting PARP-1 or MKP-1 can restore sensitivity to cisplatin in resistant cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cisplatin resistance is a major challenge in cancer therapy.
  • Mitogen-activated protein kinase phosphatase-1 (MKP-1) has been implicated in cisplatin resistance.
  • The precise mechanisms by which MKP-1 influences cisplatin resistance require further elucidation.

Purpose of the Study:

  • To investigate the role of MKP-1 in regulating poly(ADP-ribose) polymerase-1 (PARP-1) expression.
  • To determine the impact of MKP-1 on cisplatin resistance in ovarian cancer cells.
  • To explore potential therapeutic strategies targeting the MKP-1/PARP-1 pathway.

Main Methods:

  • Overexpression and silencing of MKP-1 in cancer cell lines.
  • Assessment of PARP-1 and poly(ADP-ribose) (PAR) protein levels.
  • Analysis of PARP-1 ubiquitination and protein degradation pathways.
  • Evaluation of cisplatin sensitivity in MKP-1 and PARP-1 manipulated cells.
  • Pharmacologic inhibition of PARP activity.

Main Results:

  • MKP-1 overexpression increased PARP-1 and PAR protein expression, enhancing cisplatin resistance.
  • MKP-1 downregulation suppressed PARP-1 and PAR protein levels, increasing cisplatin sensitivity.
  • Silencing MKP-1 promoted PARP-1 ubiquitination and degradation.
  • MKP-1 suppression of c-Jun N-terminal kinase 1/2 (JNK1/2) activity was linked to increased PARP-1 levels.
  • Acquired cisplatin-resistant ovarian cancer cells exhibited high MKP-1 and PARP-1 expression.
  • Silencing MKP-1 or PARP-1 resensitized resistant cells to cisplatin.
  • PARP inhibition restored cisplatin sensitivity in MKP-1 overexpressing cells.

Conclusions:

  • MKP-1 plays a critical role in cisplatin resistance by stabilizing PARP-1 protein levels, potentially via suppression of JNK1/2 signaling.
  • Targeting the MKP-1/PARP-1 axis represents a promising strategy to overcome cisplatin resistance in ovarian cancer.
  • Pharmacologic inhibition of PARP activity can effectively bypass MKP-1-mediated cisplatin resistance.

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