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Published in: International Journal of Hematology 3/2024

21-01-2024 | Multiple Myeloma | Original Article

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

Authors: Kimiko Sogabe, Shingen Nakamura, Yoshiki Higa, Hirokazu Miki, Asuka Oda, Tomoko Maruhashi, Ryohei Sumitani, Masahiro Oura, Mamiko Takahashi, Masafumi Nakamura, Yusaku Maeda, Tomoyo Hara, Hiroki Yamagami, Shiro Fujii, Kumiko Kagawa, Shuji Ozaki, Kiyoe Kurahashi, Itsuro Endo, Ken-ichi Aihara, Emiko Nakaue, Masahiro Hiasa, Jumpei Teramachi, Takeshi Harada, Masahiro Abe

Published in: International Journal of Hematology | Issue 3/2024

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Abstract

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.
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Title
Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors
Authors
Kimiko Sogabe
Shingen Nakamura
Yoshiki Higa
Hirokazu Miki
Asuka Oda
Tomoko Maruhashi
Ryohei Sumitani
Masahiro Oura
Mamiko Takahashi
Masafumi Nakamura
Yusaku Maeda
Tomoyo Hara
Hiroki Yamagami
Shiro Fujii
Kumiko Kagawa
Shuji Ozaki
Kiyoe Kurahashi
Itsuro Endo
Ken-ichi Aihara
Emiko Nakaue
Masahiro Hiasa
Jumpei Teramachi
Takeshi Harada
Masahiro Abe
Publication date
21-01-2024
Publisher
Springer Nature Singapore
Published in
International Journal of Hematology / Issue 3/2024
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-023-03705-9

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