Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.

Autor: Sogabe K; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Nakamura S; Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503, Japan. shingen@tokushima-u.ac.jp., Higa Y; Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Miki H; Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan., Oda A; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Maruhashi T; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Sumitani R; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Oura M; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Takahashi M; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Nakamura M; Department of Internal Medicine, Tokushima Prefecture Naruto Hospital, Tokushima, Japan., Maeda Y; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Hara T; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Yamagami H; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Fujii S; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Kagawa K; Department of Hematology, Tokushima Prefectural Central Hospital, Tokushima, Japan., Ozaki S; Department of Hematology, Tokushima Prefectural Central Hospital, Tokushima, Japan., Kurahashi K; Department of Community Medicine for Respirology, Hematology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Endo I; Department of Bioregulatory Sciences, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Aihara KI; Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503, Japan., Nakaue E; Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Hiasa M; Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Teramachi J; Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan., Harada T; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan., Abe M; Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan. masabe@tokushima-u.ac.jp.; Department of Hematology, Kawashima Hospital, 6-1 Kitasakoichiban-Cho, Tokushima, 770-0011, Japan. masabe@tokushima-u.ac.jp.
Jazyk: angličtina
Zdroj: International journal of hematology [Int J Hematol] 2024 Mar; Vol. 119 (3), pp. 303-315. Date of Electronic Publication: 2024 Jan 21.
DOI: 10.1007/s12185-023-03705-9
Abstrakt: 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 h at concentrations up to 400 and 1,000 nM, 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 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 h 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.
(© 2024. Japanese Society of Hematology.)
Databáze: MEDLINE
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