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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
著者
曽我部, 公子 徳島大学大学院医学研究科(医学専攻) 徳島大学 教育研究者総覧
比嘉, 佳基 Tokushima University
Oda, Asuka Tokushima University
Maruhashi, Tomoko Tokushima University
Takahashi, Mamiko Tokushima University
Nakamura, Masafumi Tokushima Prefecture Naruto Hospital
Maeda, Yusaku Tokushima University
賀川, 久美子 Tokushima Prefectural Central Hospital KAKEN研究者をさがす
尾崎, 修治 Tokushima Prefectural Central Hospital
中上, 絵美子 Tokushima University
キーワード
Multiple myeloma
Proteasome inhibitor
β5 subunit activity
PIM2
NRF2
資料タイプ
学位論文
抄録
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.
掲載誌名
International Journal of Hematology
ISSN
09255710
18653774
cat書誌ID
AA10797094
出版者
Springer Nature
119
3
開始ページ
303
終了ページ
315
発行日
2024-01-21
備考
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
出版社版DOI
出版社版URL
フルテキストファイル
言語
jpn
著者版フラグ
その他
文科省報告番号
甲第3831号
学位記番号
甲医第1609号
学位授与年月日
2024-04-25
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系
病院
歯学系