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
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Author |
Nakamura, Shingen
Tokushima University
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Higa, Yoshiki
Tokushima University
Miki, Hirokazu
Tokushima University
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Oda, Asuka
Tokushima University
Maruhashi, Tomoko
Tokushima University
Takahashi, Mamiko
Tokushima University
Nakamura, Masafumi
Tokushima Prefecture Naruto Hospital
Maeda, Yusaku
Tokushima University
Fujii, Shiro
Tokushima University
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Ozaki, Shuji
Tokushima Prefectural Central Hospital
Endo, Itsuro
Tokushima University
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Aihara, Ken-ichi
Tokushima University
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Nakaue, Emiko
Tokushima University
Hiasa, Masahiro
Tokushima University
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Teramachi, Jumpei
Okayama University
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Abe, Masahiro
Tokushima University|Kawashima Hospital
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Keywords | Multiple myeloma
Proteasome inhibitor
β5 subunit activity
PIM2
NRF2
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Content Type |
Thesis or Dissertation
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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.
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Journal Title |
International Journal of Hematology
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ISSN | 09255710
18653774
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NCID | AA10797094
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Publisher | Springer Nature
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Volume | 119
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Issue | 3
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Start Page | 303
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End Page | 315
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Published Date | 2024-01-21
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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
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TextVersion |
その他
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MEXT report number | 甲第3831号
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Diploma Number | 甲医第1609号
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Granted Date | 2024-04-25
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Degree Name |
Doctor of Medical Science
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Grantor |
Tokushima University
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departments |
Medical Sciences
University Hospital
Oral Sciences
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