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Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

Takeshi Ueda1, Masato Sasaki, Andrew J Elia

  • 1The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1.

Proceedings of the National Academy of Sciences of the United States of America
|August 4, 2010
PubMed

Insights

MAP kinase-interacting kinases (Mnk1/2) promote tumor growth, even when eIF4E phosphorylation is absent. Inhibiting Mnk1/2 suppressed tumor development in mouse models and human cell lines, suggesting Mnk1/2 as potential cancer drug targets.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • MAP kinase-interacting kinases 1 and 2 (Mnk1/2) phosphorylate eIF4E, a key regulator of cap-dependent translation initiation.
  • Despite the absence of eIF4E phosphorylation in Mnk1/2 double knockout (Mnk-DKO) mice, these animals exhibit normal development, suggesting alternative roles for Mnk1/2.
  • Tumorigenesis in the Lck-Pten mouse model (tPten(-/-)) involves enhanced eIF4E phosphorylation.

Purpose of the Study:

  • To investigate the role of Mnk1/2 in tumorigenesis within the tPten(-/-) mouse model.
  • To determine if the loss of Mnk1/2 impacts tumor development and eIF4E phosphorylation in established cancer models.
  • To evaluate Mnk1/2 as potential therapeutic targets for cancer treatment.

Main Methods:

  • Generation and analysis of tPten(-/-); Mnk-DKO mice.
  • Assessment of eIF4E phosphorylation levels in lymphomas from tPten(-/-) and tPten(-/-); Mnk-DKO mice.
  • Stable knockdown of Mnk1 in the human U87MG glioma cell line and subsequent tumor formation studies in athymic nude mice.

Main Results:

  • Loss of Mnk1/2 significantly suppressed tumorigenesis in the tPten(-/-) mouse model.
  • eIF4E phosphorylation was markedly elevated in lymphomas of tPten(-/-) mice but absent in tPten(-/-); Mnk-DKO lymphomas.
  • Stable knockdown of Mnk1 dramatically reduced tumor formation of U87MG cells in vivo.

Conclusions:

  • Mnk1/2 play a critical oncogenic role in tumor development.
  • Inactivation of Mnk1/2 can suppress tumorigenesis, indicating their potential as anticancer drug targets.
  • Targeting Mnk1/2 may offer a therapeutic strategy with minimal side effects due to normal development in their absence.

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