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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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Oncogenic MNK signalling regulates the metastasis suppressor NDRG1

Shuye Tian1,2, Xuemin Wang1,2, Christopher G Proud1,2

  • 1Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide SA5000, Australia.

Oncotarget
|May 26, 2017
PubMed

Insights

The oncogenic MAP kinase-interacting kinase (MNK) pathway regulates N-myc down-regulated gene 1 (NDRG1) expression and phosphorylation, impacting breast cancer cell migration and metastasis. This reveals novel signaling connections crucial for tumor biology.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • N-myc down-regulated gene 1 (NDRG1) protein suppresses tumor metastasis.
  • NDRG1 is phosphorylated by serum and glucocorticoid-regulated kinase 1 (SGK1).
  • The MAP kinase-interacting kinase (MNK) pathway is a potential cancer therapy target.

Purpose of the Study:

  • To investigate the regulation of NDRG1 by the MNK pathway.
  • To elucidate the roles of MNK and SGK1 in cell migration and metastasis.
  • To uncover novel signaling connections in tumor biology.

Main Methods:

  • Investigated NDRG1 expression and phosphorylation in breast cancer cells following MNK inhibition.
  • Utilized knockout cell lines (MNK1, MNK2) to assess specific kinase roles.
  • Performed in vitro kinase assays to determine direct phosphorylation events.
  • Examined the effects of MNK and SGK1 inhibition on cell migration and invasion.

Main Results:

  • MNK inhibition increased NDRG1 protein and mRNA levels and decreased NDRG1 phosphorylation, specifically via MNK1.
  • MNK1 cannot directly phosphorylate NDRG1, suggesting indirect regulation.
  • SGK1 phosphorylates MNK1, repressing its activity.
  • MNK inhibition impaired cell migration regardless of NDRG1 levels, while SGK1 inhibition's effect was dependent on NDRG1 levels.

Conclusions:

  • The MNK signaling pathway regulates NDRG1 at both transcriptional and post-translational levels.
  • MNKs and SGK1 influence cell migration and invasion through distinct mechanisms.
  • Novel connections between MNK, SGK1, and NDRG1 signaling pathways in tumor biology were identified.
Keywords:
MNK1NDRG1SGKbreast cancermigration

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