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

• Published in: International journal of hematology Vol. 119; no. 3; pp. 303 - 315
• Main Authors: Sogabe, Kimiko, Nakamura, Shingen, Higa, Yoshiki, Miki, Hirokazu, Oda, Asuka, Maruhashi, Tomoko, Sumitani, Ryohei, Oura, Masahiro, Takahashi, Mamiko, Nakamura, Masafumi, Maeda, Yusaku, Hara, Tomoyo, Yamagami, Hiroki, Fujii, Shiro, Kagawa, Kumiko, Ozaki, Shuji, Kurahashi, Kiyoe, Endo, Itsuro, Aihara, Ken-ichi, Nakaue, Emiko, Hiasa, Masahiro, Teramachi, Jumpei, Harada, Takeshi, Abe, Masahiro
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.03.2024; Springer Nature B.V
• Subjects: Accumulation; AKT protein; Bortezomib; Cycloheximide; Gene expression; Hematology; Inhibitors; Medicine; Medicine & Public Health; Multiple myeloma; Oncology; Original Article; Pharmacodynamics; Pharmacokinetics; Proteasome inhibitors; Proteasomes; Protein biosynthesis; Protein synthesis; Puromycin; PIM2; NRF2; Proteasome inhibitor; Multiple myeloma; β5 subunit activity
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-023-03705-9

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.