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

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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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Acknowledgements

This work was supported by JSPS KAKENHI Grant Numbers JP22K08455, JP21H0311, JP22K19626, JP17H05104, JP19K22719, and JP23H03101; the Research Clusters program of Tokushima University (2202003, T.H.); and the Japanese Society of Hematology Research Grants (T.H. and H.M). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Kimiko Sogabe, Asuka Oda, Tomoko Maruhashi, Ryohei Sumitani, Masahiro Oura, Mamiko Takahashi, Yusaku Maeda, Tomoyo Hara, Hiroki Yamagami, Shiro Fujii, Takeshi Harada & Masahiro Abe

  2. Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503, Japan

    Shingen Nakamura & Ken-ichi Aihara

  3. Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Yoshiki Higa, Emiko Nakaue & Masahiro Hiasa

  4. Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan

    Hirokazu Miki

  5. Department of Internal Medicine, Tokushima Prefecture Naruto Hospital, Tokushima, Japan

    Masafumi Nakamura

  6. Department of Hematology, Tokushima Prefectural Central Hospital, Tokushima, Japan

    Kumiko Kagawa & Shuji Ozaki

  7. Department of Community Medicine for Respirology, Hematology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Kiyoe Kurahashi

  8. Department of Bioregulatory Sciences, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Itsuro Endo

  9. Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    Jumpei Teramachi

  10. Department of Hematology, Kawashima Hospital, 6-1 Kitasakoichiban-Cho, Tokushima, 770-0011, Japan

    Masahiro Abe

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  1. Kimiko Sogabe
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  2. Shingen Nakamura
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Contributions

KS, SN, TH, and MA contributed to the study design. KS, YH, OA, and TM conducted experiments. SN, HM, RS, MO, MT, MN, YM, SF, KK, SO, and TH contributed to the collection of clinical samples. TH, HY, KK, IE, KA, EN, MH, and TJ reviewed data. KS, SN, TH, and MA wrote and revised the manuscript. All authors were involved in the analyses and interpretation of data. All authors read and approved the submitted version of the manuscript.

Corresponding authors

Correspondence to Shingen Nakamura or Masahiro Abe.

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Conflict of interest

T.H. received research funding from GlaxoSmithKline. M.A. received research funding from Chugai Pharmaceutical, Sanofi K.K., Pfizer Seiyaku K.K., Kyowa Hakko Kirin, Janssen Pharma K.K., Takeda Pharmaceutical, Teijin Pharma, and Ono Pharmaceutical, and honoraria from Daiichi Sankyo Company. The other authors declare no competing financial interests.

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Sogabe, K., Nakamura, S., Higa, Y. et al. Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors. Int J Hematol 119, 303–315 (2024). https://doi.org/10.1007/s12185-023-03705-9

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