VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines

Nami Kurozumi, Takayuki Tsujioka, Mamoru Ouchida, Kanae Sakakibara, Takako Nakahara, Shin ichiro Suemori, Masaki Takeuchi, Akira Kitanaka, Misako Shibakura, Kaoru Tohyama

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3302-3313
Number of pages12
JournalCancer Science
Volume112
Issue number8
DOIs
Publication statusPublished - Aug 2021

Keywords

  • VLX1570
  • acute myeloid leukemia
  • endoplasmic reticulum stress
  • proteasome deubiquitinase
  • reactive oxygen species

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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