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Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia
T cell acute lymphoblastic leukemia (T-ALL), a neoplasm derived from T cell lineage-committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609462/ https://www.ncbi.nlm.nih.gov/pubmed/37800623 http://dx.doi.org/10.3892/ijo.2023.5576 |
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author | Chang, Yoon Soo Gills, Joell J. Kawabata, Shigeru Onozawa, Masahiro Della Gatta, Giusy Ferrando, Adolfo A. Aplan, Peter D. Dennis, Phillip A. |
author_facet | Chang, Yoon Soo Gills, Joell J. Kawabata, Shigeru Onozawa, Masahiro Della Gatta, Giusy Ferrando, Adolfo A. Aplan, Peter D. Dennis, Phillip A. |
author_sort | Chang, Yoon Soo |
collection | PubMed |
description | T cell acute lymphoblastic leukemia (T-ALL), a neoplasm derived from T cell lineage-committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ-secretase. γ-secretase inhibitors (GSIs) are a NOTCH-targeted therapy for T-ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ-secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH-associated T-ALL. The present study assessed the efficacy of nelfinavir against T-ALL cells and investigated mechanisms of action in vitro and in preclinical treatment studies using a SCL-LMO1 transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ-secretase activity as well as the NOTCH1 pathway, thus suppressing T-ALL cell viability. Additionally, microarray analysis of nelfinavir-treated T-ALL cells showed that nelfinavir upregulated mRNA levels of CHAC1 (glutathione-specific γ-glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (SESN2; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T-ALL cells. Moreover, nelfinavir suppressed NOTCH1 mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating NOTCH1 mRNA expression, upregulating CHAC1 and suppressing γ-secretase via presenilin 1 inhibition and the mTOR pathway by upregulating SESN2 via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T-ALL in an SCL-LMO1 transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T-ALL. |
format | Online Article Text |
id | pubmed-10609462 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-106094622023-10-28 Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia Chang, Yoon Soo Gills, Joell J. Kawabata, Shigeru Onozawa, Masahiro Della Gatta, Giusy Ferrando, Adolfo A. Aplan, Peter D. Dennis, Phillip A. Int J Oncol Articles T cell acute lymphoblastic leukemia (T-ALL), a neoplasm derived from T cell lineage-committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ-secretase. γ-secretase inhibitors (GSIs) are a NOTCH-targeted therapy for T-ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ-secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH-associated T-ALL. The present study assessed the efficacy of nelfinavir against T-ALL cells and investigated mechanisms of action in vitro and in preclinical treatment studies using a SCL-LMO1 transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ-secretase activity as well as the NOTCH1 pathway, thus suppressing T-ALL cell viability. Additionally, microarray analysis of nelfinavir-treated T-ALL cells showed that nelfinavir upregulated mRNA levels of CHAC1 (glutathione-specific γ-glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (SESN2; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T-ALL cells. Moreover, nelfinavir suppressed NOTCH1 mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating NOTCH1 mRNA expression, upregulating CHAC1 and suppressing γ-secretase via presenilin 1 inhibition and the mTOR pathway by upregulating SESN2 via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T-ALL in an SCL-LMO1 transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T-ALL. D.A. Spandidos 2023-10-02 /pmc/articles/PMC10609462/ /pubmed/37800623 http://dx.doi.org/10.3892/ijo.2023.5576 Text en Copyright: © Chang et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Chang, Yoon Soo Gills, Joell J. Kawabata, Shigeru Onozawa, Masahiro Della Gatta, Giusy Ferrando, Adolfo A. Aplan, Peter D. Dennis, Phillip A. Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia |
title | Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia |
title_full | Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia |
title_fullStr | Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia |
title_full_unstemmed | Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia |
title_short | Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia |
title_sort | inhibition of the notch and mtor pathways by nelfinavir as a novel treatment for t cell acute lymphoblastic leukemia |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609462/ https://www.ncbi.nlm.nih.gov/pubmed/37800623 http://dx.doi.org/10.3892/ijo.2023.5576 |
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