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Annals of Hematology

Open Access 04-01-2025 | Multiple Myeloma | Research

Metabolic reprogramming induced by PSMA4 overexpression facilitates bortezomib resistance in multiple myeloma

Authors: Han Yu, Chengli Wu, Jie He, Yajun Zhang, Qiqi Cao, Hongyan Lan, Hongshan Li, Chengyang Xu, Chen Chen, Rong Li, Bo Zheng

Published in: Annals of Hematology

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Abstract

Multiple myeloma(MM) remains incurable with high relapse and chemoresistance rates. Differentially expressed genes(DEGs) between newly diagnosed myeloma and secondary plasma cell leukemia(sPCL) were subjected to a weighted gene co-expression network analysis(WGCNA). Drug resistant myeloma cell lines were established. Seahorse XF analyzer was applied to detect the metabolism reprogramming associated with the hub gene. The metabolic relevance and the underlying mechanism of the hub gene in myeloma resistance were explored via in vitro experiments. A total of 1310 DEGs were used to construct five co-expression modules. Gene function enrichment analysis demonstrated that candidate hub genes were closely related to oxidative phosphorylation. We performed prognostic analysis and identified PSMA4 as the key hub gene related to the extramedullary invasion of myeloma. The in vitro experiments demonstrated bortezomib resistant myeloma cell lines exhibited high PSMA4 expression, improved oxidative phosphorylation activity with increased ROS level. PSMA4 knockdown re-sensitize resistant myeloma cells via suppressing oxidative phosphorylation activity. Further investigation revealed that PSMA4 induced a hypoxia state which activated the HIF-1α signaling pathway. PSMA4 induces metabolic reprogramming by improving oxidative phosphorylation activity which accounts for the hypoxia state in myeloma cell. The activated HIF-1α signaling pathway causes bortezomib resistance via promoting anti-apoptotic activity in myeloma.
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Literature
1.
2.
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J et al (2012) Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 26(1):149–157CrossRefPubMed
3.
Bianchi G, Oliva L, Cascio P, Pengo N, Fontana F, Cerruti F et al (2009) The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood 113(13):3040–3049CrossRefPubMed
4.
Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M et al (2007) Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 67(4):1783–1792CrossRefPubMed
5.
Ocio EM, Mateos MV, San-Miguel JF (2012) Novel agents derived from the currently approved treatments for MM: novel proteasome inhibitors and novel IMIDs. Expert Opin Investig Drugs 21(8):1075–1087CrossRefPubMed
6.
7.
Koomen DC, Meads MB, Magaletti DM, Guingab-Cagmat JD, Oliveira PS, Fang B et al (2021) Metabolic changes are associated with melphalan resistance in multiple myeloma. J Proteome Res 20(6):3134–3149CrossRefPubMedPubMedCentral
8.
Maiso P, Huynh D, Moschetta M, Sacco A, Aljawai Y, Mishima Y et al (2015) Metabolic signature identifies novel targets for drug resistance in multiple myeloma. Cancer Res 75(10):2071–2082CrossRefPubMedPubMedCentral
9.
Wegiel B, Vuerich M, Daneshmandi S, Seth P (2018) Metabolic switch in the tumor microenvironment determines immune responses to anti-cancer therapy. Front Oncol 8:284CrossRefPubMedPubMedCentral
10.
11.
Rehman SK, Haynes J, Collignon E, Brown KR, Wang Y, Nixon AML et al (2021) Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 184(1):226–242 (e21)CrossRefPubMed
12.
Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE et al (2017) MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab 26(4):633–647 (e7)CrossRefPubMedPubMedCentral
13.
Foo J, Bellot G, Pervaiz S, Alonso S (2022) Mitochondria-mediated oxidative stress during viral infection. Trends Microbiol 30(7):679–692CrossRefPubMed
14.
Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D et al (2012) Bortezomib-Thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 120(1):9–19CrossRefPubMed
15.
Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV et al (2017) Multiple myeloma. Nat Rev Dis Primers 3:17046CrossRefPubMed
16.
Kubiczkova L, Pour L, Sedlarikova L, Hajek R, Sevcikova S (2014) Proteasome inhibitors - molecular basis and current perspectives in multiple myeloma. J Cell Mol Med 18(6):947–961CrossRefPubMedPubMedCentral
17.
Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR et al (2008) Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112(6):2489–2499CrossRefPubMed
18.
Zhang XD, Baladandayuthapani V, Lin H, Mulligan G, Li B, Esseltine DW et al (2016) Tight junction protein 1 modulates proteasome capacity and proteasome inhibitor sensitivity in multiple myeloma via EGFR/JAK1/STAT3 signaling. Cancer Cell 29(5):639–652CrossRefPubMedPubMedCentral
19.
Li T, Xiao P, Qiu D, Yang A, Chen Q, Lin J et al (2024) NCX1/Ca(2+) promotes autophagy and decreases bortezomib activity in multiple myeloma through non-canonical NFkappaB signaling pathway. Cell Commun Signal 22(1):258CrossRefPubMedPubMedCentral
20.
Spaan I, van Nieuwenhuijzen N, Kimman T, Rockx-Brouwer D, Tieland RG, Maurice MM et al (2023) Wnt inhibitors reduce the unfolded protein response and enhance bortezomib-induced cell death in multiple myeloma. Blood Adv 7(7):1103–1107CrossRefPubMed
21.
Vdovin A, Jelinek T, Zihala D, Sevcikova T, Durech M, Sahinbegovic H et al (2022) The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma. Nat Commun 13(1):6820CrossRefPubMedPubMedCentral
22.
Barrio S, Stuhmer T, Da-Via M, Barrio-Garcia C, Lehners N, Besse A et al (2019) Spectrum and functional validation of PSMB5 mutations in multiple myeloma. Leukemia 33(2):447–456CrossRefPubMed
23.
Martinez-Reyes I, Chandel NS (2021) Cancer metabolism: looking forward. Nat Rev Cancer 21(10):669–680CrossRefPubMed
24.
25.
Zaal EA, de Grooth HJ, Oudaert I, Langerhorst P, Levantovsky S, van Slobbe GJJ et al (2022) Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma. Mol Omics 18(1):19–30CrossRefPubMed
26.
Zaal EA, Wu W, Jansen G, Zweegman S, Cloos J, Berkers CR (2017) Bortezomib resistance in multiple myeloma is associated with increased serine synthesis. Cancer Metab 5:7CrossRefPubMedPubMedCentral
27.
Soriano GP, Besse L, Li N, Kraus M, Besse A, Meeuwenoord N et al (2016) Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism. Leukemia 30(11):2198–2207CrossRefPubMedPubMedCentral
28.
29.
Li RL, He LY, Zhang Q, Liu J, Lu F, Duan HX et al (2020) HIF-1alpha is a potential molecular target for herbal medicine to treat diseases. Drug Des Devel Ther 14:4915–4949CrossRefPubMedPubMedCentral
30.
Luo S, Jiang Y, Anfu Z, Zhao Y, Wu X, Li M et al (2022) Targeting hypoxia-inducible factors for breast cancer therapy: a narrative review. Front Pharmacol 13:1064661CrossRefPubMedPubMedCentral
Metadata
Title
Metabolic reprogramming induced by PSMA4 overexpression facilitates bortezomib resistance in multiple myeloma
Authors
Han Yu
Chengli Wu
Jie He
Yajun Zhang
Qiqi Cao
Hongyan Lan
Hongshan Li
Chengyang Xu
Chen Chen
Rong Li
Bo Zheng
Publication date
04-01-2025
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-024-06163-3

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