Mutant IDH1 inhibitors activate pSTAT3-Y705 leading to an increase in BCAT1 and YKL-40 levels in mutant IDH1-expressing cells.
Biochim Biophys Acta Mol Cell Res
; 1868(11): 119114, 2021 10.
Article
en En
| MEDLINE
| ID: mdl-34329662
ABSTRACT
IDH1 mutations are frequent and early events in gliomas. Mutant IDH1 produces D-2HG that causes epigenetic changes by increasing histone and DNA methylations, thereby contributing to tumor growth. Mutant IDH1 rewires metabolism and endows a few therapeutic vulnerabilities in cells. But, mutant IDH1 inhibitor(s) treatments reverse these therapeutic vulnerabilities by increasing cell growth. Nevertheless, it is unclear how mutant IDH1 inhibitor(s) increases cell growth. As mutant IDH1 inhibitor(s) increase cell growth, therefore we asked whether mutant IDH1 inhibitor(s) activate oncogenes in mutant IDH1-expressing cells. To answer this question, we used allosteric mutant IDH1 inhibitors to treat mutant IDH1-expressing HT1080 cells, and examined for activation of oncogenes by assessing the levels of our read-outs BCAT1 and YKL-40. We found that mutant IDH1 inhibitors' treatments increased BCAT1 and YKL-40 levels in HT1080 cells. Next, we observed that mutant IDH1 inhibitors activated STAT3 by phosphorylation at Tyr-705 position (pSTAT3-Y705) and its nuclear translocation. Upon examining the molecular mechanism of pSTAT3-Y705 activation in mutant IDH1 inhibitor-treated cells, we found that mutant IDH1 strongly bound STAT3, but mutant IDH1 inhibitor treatment decreased mutant IDH1-STAT3 binding. Furthermore, we observed that STAT3-knockdown and pharmacological inhibition of STAT3 attenuated the mutant IDH1 inhibitor-mediated increase in BCAT1 and YKL-40 levels, whereas STAT3 overexpression and Interleukin-6 (STAT3 activator) treatments increased BCAT1 and YKL-40 levels. We conclude that mutant IDH1 inhibitors activate the oncogenic transcription factor-STAT3 leading to an increase in BCAT1 and YKL-40 levels in mutant IDH1-expressing cells.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tirosina
/
Inhibidores Enzimáticos
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Factor de Transcripción STAT3
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Proteína 1 Similar a Quitinasa-3
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Transaminasas
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Isocitrato Deshidrogenasa
Límite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta Mol Cell Res
Año:
2021
Tipo del documento:
Article
País de afiliación:
India