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VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines
A novel proteasome deubiquitinase inhibitor, VLX1570, has been highlighted as a promising therapeutic agent mainly for lymphoid neoplasms and solid tumors. We examined in vitro effects of VLX1570 on eight myeloid and three lymphoid leukemia cell lines. From cell culture studies, 10 out of 11 cell li...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353915/ https://www.ncbi.nlm.nih.gov/pubmed/34032336 http://dx.doi.org/10.1111/cas.14982 |
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author | Kurozumi, Nami Tsujioka, Takayuki Ouchida, Mamoru Sakakibara, Kanae Nakahara, Takako Suemori, Shin‐ichiro Takeuchi, Masaki Kitanaka, Akira Shibakura, Misako Tohyama, Kaoru |
author_facet | Kurozumi, Nami Tsujioka, Takayuki Ouchida, Mamoru Sakakibara, Kanae Nakahara, Takako Suemori, Shin‐ichiro Takeuchi, Masaki Kitanaka, Akira Shibakura, Misako Tohyama, Kaoru |
author_sort | Kurozumi, Nami |
collection | PubMed |
description | A novel proteasome deubiquitinase inhibitor, VLX1570, has been highlighted as a promising therapeutic agent mainly for lymphoid neoplasms and solid tumors. We examined in vitro effects of VLX1570 on eight myeloid and three lymphoid leukemia cell lines. From cell culture studies, 10 out of 11 cell lines except K562 were found to be susceptible to VLX1570 treatment and it inhibited cell growth mainly by apoptosis. Next, to identify the signaling pathways associated with apoptosis, we performed gene expression profiling using HL‐60 with or without 50 nmol/L of VLX1570 for 3 hours and demonstrated that VLX1570 induced the genetic pathway involved in “heat shock transcription factor 1 (HSF1) activation”, “HSF1 dependent transactivation”, and “Regulation of HSF1 mediated heat shock response”. VLX1570 increased the amount of high molecular weight polyubiquitinated proteins and the expression of HSP70 as the result of the suppression of ubiquitin proteasome system, the expression of heme oxygenase‐1, and the amount of phosphorylation in JNK and p38 associated with the generation of reactive oxygen species (ROS) induced apoptosis and the amount of phosphorylation in eIF2α, inducing the expression of ATF4 and endoplasmic reticulum (ER) stress dependent apoptosis protein, CHOP, and the amount of phosphorylation slightly in IRE1α, leading to increased expression of XBP‐1s in leukemia cell lines. In the present study, we demonstrate that VLX1570 induces apoptosis and exerts a potential anti‐leukemic effect through the generation of ROS and induction of ER stress in leukemia cell lines. |
format | Online Article Text |
id | pubmed-8353915 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83539152021-08-15 VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines Kurozumi, Nami Tsujioka, Takayuki Ouchida, Mamoru Sakakibara, Kanae Nakahara, Takako Suemori, Shin‐ichiro Takeuchi, Masaki Kitanaka, Akira Shibakura, Misako Tohyama, Kaoru Cancer Sci Original Articles A novel proteasome deubiquitinase inhibitor, VLX1570, has been highlighted as a promising therapeutic agent mainly for lymphoid neoplasms and solid tumors. We examined in vitro effects of VLX1570 on eight myeloid and three lymphoid leukemia cell lines. From cell culture studies, 10 out of 11 cell lines except K562 were found to be susceptible to VLX1570 treatment and it inhibited cell growth mainly by apoptosis. Next, to identify the signaling pathways associated with apoptosis, we performed gene expression profiling using HL‐60 with or without 50 nmol/L of VLX1570 for 3 hours and demonstrated that VLX1570 induced the genetic pathway involved in “heat shock transcription factor 1 (HSF1) activation”, “HSF1 dependent transactivation”, and “Regulation of HSF1 mediated heat shock response”. VLX1570 increased the amount of high molecular weight polyubiquitinated proteins and the expression of HSP70 as the result of the suppression of ubiquitin proteasome system, the expression of heme oxygenase‐1, and the amount of phosphorylation in JNK and p38 associated with the generation of reactive oxygen species (ROS) induced apoptosis and the amount of phosphorylation in eIF2α, inducing the expression of ATF4 and endoplasmic reticulum (ER) stress dependent apoptosis protein, CHOP, and the amount of phosphorylation slightly in IRE1α, leading to increased expression of XBP‐1s in leukemia cell lines. In the present study, we demonstrate that VLX1570 induces apoptosis and exerts a potential anti‐leukemic effect through the generation of ROS and induction of ER stress in leukemia cell lines. John Wiley and Sons Inc. 2021-06-13 2021-08 /pmc/articles/PMC8353915/ /pubmed/34032336 http://dx.doi.org/10.1111/cas.14982 Text en © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Kurozumi, Nami Tsujioka, Takayuki Ouchida, Mamoru Sakakibara, Kanae Nakahara, Takako Suemori, Shin‐ichiro Takeuchi, Masaki Kitanaka, Akira Shibakura, Misako Tohyama, Kaoru VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines |
title | VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines |
title_full | VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines |
title_fullStr | VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines |
title_full_unstemmed | VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines |
title_short | VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines |
title_sort | vlx1570 induces apoptosis through the generation of ros and induction of er stress on leukemia cell lines |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353915/ https://www.ncbi.nlm.nih.gov/pubmed/34032336 http://dx.doi.org/10.1111/cas.14982 |
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