HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia
| Autor: | Koshi Akahane, Marc R. Mansour, Daniel J. DeAngelo, Takaomi Sanda, David M. Weinstock, Thomas Radimerski, A T Look |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research T cell Apoptosis Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Article 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation TYK2 Kinase Cell Line Tumor Proto-Oncogene Proteins hemic and lymphatic diseases Heat shock protein medicine Humans HSP90 Heat-Shock Proteins Bcl-2-Like Protein 11 biology Membrane Proteins Isoxazoles Resorcinols Hematology medicine.disease Hsp90 Cell biology Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Oncology 030220 oncology & carcinogenesis biology.protein Cancer research bcl-Associated Death Protein Apoptosis Regulatory Proteins |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | We previously found that TYK2 tyrosine kinase signaling through its downstream effector phospho-STAT1 (p-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 p-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. |
| Databáze: | OpenAIRE |
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