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ID 119384
Title Alternative
PIM2とNRF2の急速な蓄積とβ5サブユニット活性の回復は多発性骨髄腫細胞のプロテアソーム阻害薬への感受性を減弱させる
Mechanisms of myeloma cell resistance to proteasome inhibitors
Author
Higa, Yoshiki Tokushima University
Oda, Asuka Tokushima University
Maruhashi, Tomoko Tokushima University
Takahashi, Mamiko Tokushima University
Nakamura, Masafumi Tokushima Prefecture Naruto Hospital
Maeda, Yusaku Tokushima University
Kagawa, Kumiko Tokushima Prefectural Central Hospital KAKEN Search Researchers
Ozaki, Shuji Tokushima Prefectural Central Hospital
Nakaue, Emiko Tokushima University
Keywords
Multiple myeloma
Proteasome inhibitor
β5 subunit activity
PIM2
NRF2
Content Type
Thesis or Dissertation
Description
Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 hour at concentrations up to 400 and 1,000nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 hours in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 hours in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.
Journal Title
International Journal of Hematology
ISSN
09255710
18653774
NCID
AA10797094
Publisher
Springer Nature
Volume
119
Issue
3
Start Page
303
End Page
315
Published Date
2024-01-21
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Kimiko Sogabeの学位論文として提出され,学位審査・授与の対象となっている。
論文本文は2025-01-21以降公開予定
This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use (https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms), but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s12185-023-03705-9
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
jpn
TextVersion
その他
MEXT report number
甲第3831号
Diploma Number
甲医第1609号
Granted Date
2024-04-25
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital
Oral Sciences