GSK-3beta inhibition: at the crossroad between Akt and mTOR constitutive activation to enhance cyclin D1 protein stability in mantle cell lymphoma

Cell Cycle. 2008 Sep 15;7(18):2813-6. doi: 10.4161/cc.7.18.6733. Epub 2008 Sep 5.

Abstract

Strategies able to downregulate the aberrant expression of cyclin D1 may prove of therapeutic relevance in cancer patients. This is particularly true for mantle cell lymphoma (MCL) in which cyclin D1 is overexpressed as a consequence of the t(11;14)(q13;q32) translocation. We have recently demonstrated that an increased cyclin D1 stability also contributes to the high levels of this protein observed in MCL cells. This effect is mediated by a constitutive activation of PI3-K/Akt, which keeps GSK-3beta inhibited. Here we show that inhibition of PI3-K/Akt induces a 40% decrease of cyclin D1 half-life as a result of accumulation of the dephosphorylated/active form of GSK-3beta within the nucleus, where this kinase can phosphorylate cyclin D1 on Thr286 thereby promoting its nuclear export. Translocation of cyclin D1 into the cytoplasm is mediated by the nuclear exportin CRM1, whose association with cyclin D1 increases following PI3-K/Akt inhibition. Notably, rapamycin downregulated GSK-3beta Ser9 phosphorylation with concurrent nuclear export of cyclin D1 only in MCL cells in which GSK-3beta is under the control of mTOR. These findings suggest that the ability to downregulate cyclin D1 through GSK-3beta may identify subsets of MCL patients who may benefit from the treatment with mTOR inhibitors and stimulate further studies to assess whether the inability to affect GSK-3beta activity may constitute a clinically relevant resistance factor to mTOR inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / enzymology
  • Chromones / pharmacology
  • Cyclin D1 / metabolism*
  • Enzyme Activation / drug effects
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Half-Life
  • Humans
  • Karyopherins / metabolism
  • Lymphoma, Mantle-Cell / enzymology*
  • Lymphoma, Mantle-Cell / pathology
  • Mitogen-Activated Protein Kinases / metabolism
  • Morpholines / pharmacology
  • Phosphothreonine / metabolism
  • Protein Binding / drug effects
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • TOR Serine-Threonine Kinases
  • Thermodynamics

Substances

  • Chromones
  • Karyopherins
  • Morpholines
  • Receptors, Cytoplasmic and Nuclear
  • exportin 1 protein
  • Phosphothreonine
  • Cyclin D1
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Glycogen Synthase Kinase 3