HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia

Details

• Alternative Title:
  Leukemia
• Personal Author:
  Akahane, Koshi ; Sanda, Takaomi ; Mansour, Marc R. ; Radimerski, Thomas ; DeAngelo, Daniel J. ; Weinstock, David M. ; Look, A. Thomas
• Description:
  We previously found that tyrosine kinase 2 (TYK2) signaling through its downstream effector phospho-STAT1 acts to upregulate BCL2, which in turn mediates aberrant survival of T-cell acute lymphoblastic leukemia (T-ALL) cells. Here we show that pharmacologic inhibition of heat shock protein 90 (HSP90) with a small-molecule inhibitor, NVP-AUY922 (AUY922), leads to rapid degradation of TYK2 and apoptosis in T-ALL cells. STAT1 protein levels were not affected by AUY922 treatment, but phospho-STAT1 (Tyr-701) levels rapidly became undetectable, consistent with a block in signaling downstream of TYK2. BCL2 expression was downregulated after AUY922 treatment, and although this effect was necessary for AUY922-induced apoptosis, it was not sufficient because many T-ALL cell lines were resistant to ABT-199, a specific inhibitor of BCL2. Unlike ABT-199, AUY922 also upregulated the proapoptotic proteins BIM and BAD, whose increased expression was required for AUY922-induced apoptosis. Thus, the potent cytotoxicity of AUY922 involves the synergistic combination of BCL2 downregulation coupled with upregulation of the proapoptotic proteins BIM and BAD. This two-pronged assault on the mitochondrial apoptotic machinery identifies HSP90 inhibitors as promising drugs for targeting the TYK2-mediated prosurvival signaling axis in T-ALL cells.
• Subjects:
  Apoptosis Apoptosis Regulatory Proteins Article Bcl-Associated Death Protein Cell Line, Tumor HSP90 Heat-Shock Proteins Humans Isoxazoles Membrane Proteins Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Proto-Oncogene Proteins Proto-Oncogene Proteins C-bcl-2 Resorcinols TYK2 Kinase

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• Source:
  Leukemia. 30(1):219-228.
• Pubmed ID:
  26265185
• Pubmed Central ID:
  PMC4703488
• Document Type:
  Journal Article
• Funding:
  P01 CA109901/CA/NCI NIH HHS/United States ; R01 CA176746/CA/NCI NIH HHS/United States ; 5R01CA176746/CA/NCI NIH HHS/United States ; 5P01CA109901/CA/NCI NIH HHS/United States ; U48 DP005014/DP/NCCDPHP CDC HHS/United States
• Volume:
  30
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:21acfc36a9adb4780aa7f60ab702e287de6d7176a17c582804cad3d52887958d
• Download URL:
  https://stacks.cdc.gov/view/cdc/42087/cdc_42087_DS1.pdf
• File Type:
  [PDF - 1.88 MB ]