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GILZ inhibits the mTORC2/AKT pathway in BCR-ABL(+) cells

S Joha1, A-L Nugues, D Hétuin

  • 1Institut de Recherche sur le Cancer de Lille, Université Lille-Nord de France, Lille, France.

Oncogene
|August 2, 2011
PubMed

Insights

Glucocorticoid-induced leucine zipper protein (GILZ) combats chronic myeloid leukemia (CML) by inhibiting the mTORC2/AKT pathway, overcoming resistance to tyrosine kinase inhibitors (TKIs) like imatinib and dasatinib.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Chronic myeloid leukemia (CML) malignancy stems from BCR-ABL oncoprotein's tyrosine kinase activity.
  • Tyrosine kinase inhibitors (TKIs) are effective but resistance, particularly in advanced CML, is a significant clinical challenge.
  • BCR-ABL signaling activates pro-survival pathways like phosphoinositide 3-kinase/AKT.

Purpose of the Study:

  • To investigate the role of glucocorticoid-induced leucine zipper protein (GILZ) in modulating TKI resistance in CML.
  • To elucidate the molecular mechanisms by which GILZ affects BCR-ABL signaling and CML cell survival.

Main Methods:

  • Utilized mouse and human CML models.
  • Investigated GILZ interaction with mTORC1 and mTORC2 complexes.
  • Assessed AKT phosphorylation, FoxO3a transcriptional activity, and Bim expression.
  • Analyzed CD34(+) stem cells from relapsing CML patients.

Main Results:

  • GILZ inactivates the mammalian target of rapamycin complex-2 (mTORC2)/AKT pathway, suppressing tumor growth.
  • GILZ directly binds to mTORC2, inhibiting AKT phosphorylation at Ser473.
  • GILZ promotes FoxO3a-mediated transcription of the pro-apoptotic protein Bim.
  • Glucocorticoids and imatinib induced GILZ-mediated apoptosis and mTORC2 inhibition in CML stem cells.

Conclusions:

  • GILZ acts as a key inhibitor of the mTORC2 pathway in BCR-ABL(+) cells.
  • GILZ modulation of mTORC2 signaling represents a novel mechanism influencing TKI sensitivity in CML.
  • Targeting GILZ or the mTORC2 pathway may offer strategies to overcome TKI resistance in CML.

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