Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation.

Rob Ruijtenbeek,Johan Garssen,Esther A Zaal,Frank A Redegeld,Jing Chen,Celia R Berkers

doi:10.3390/cells10092287

Rob Ruijtenbeek, Johan Garssen + Show 4 more

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https://doi.org/10.3390/cells10092287

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Abstract

Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells. In the current study, both transcriptome and metabolome analysis were performed to comprehensively evaluate the underlying mechanism. It was demonstrated that pretreating MM cells with DHA/EPA before bortezomib potently decreased the cellular glutathione (GSH) level and altered the expression of the related metabolites and key enzymes in GSH metabolism, whereas simultaneous treatment only showed minor effects on these factors, thereby suggesting the critical role of GSH degradation in overcoming bortezomib resistance in MM cells. Moreover, RNA-seq results revealed that the nuclear factor erythroid 2-related factor 2 (NRF2)-activating transcription factor 3/4 (ATF3/4)-ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway may be implicated as the central player in the GSH degradation. Pathways of necroptosis, ferroptosis, p53, NRF2, ATF4, WNT, MAPK, NF-κB, EGFR, and ERK may be connected to the tumor suppressive effect caused by pretreatment of DHA/EPA prior to bortezomib. Collectively, this work implicates GSH degradation as a potential therapeutic target in MM and provides novel mechanistic insights into its significant role in combating bortezomib resistance.

Highlights

MM, the second most prevalent hematological malignancy, is charactered by the clonal proliferation of antibody-secreting plasma cells in the bone marrow [1]
The Venn diagram showed that seven common genes were differentially expressed after treatment with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), or bortezomib (Figure 1B), which were represented in the volcano plots (Figure 1C)
Our result showed that S-adenosylmethionine (SAM), a major methyl donor for most cellular methylation reactions that produce S-adenosylhomocysteine (SAH) as a by-product for homocysteine synthesis, was substantially increased by pretreatment but was decreased by simultaneous treatment compared to bortezomib treatment (Figure 4G), indirectly indicating the activation of methionine metabolism by DHA/EPA pretreatment in OPM2 cells

Summary

Introduction

MM, the second most prevalent hematological malignancy, is charactered by the clonal proliferation of antibody-secreting plasma cells in the bone marrow [1]. Given that MM cells inevitably produce large amounts of misfolded or unfolded proteins, proteasome inhibitor-based drugs are widely used as first line therapy for MM [2]. Most patients invariably relapse after an effective initial treatment or become refractory, mainly due to the development of drug resistance [5]. Recently, daratumumab, a CD38-targeting human monoclonal antibody, in combination with bortezomib, has been approved by the FDA for relapsed/refractory MM patients after bortezomib-based therapy [6]. It remains a highly unmet need for developing novel drugs or combination therapeutic strategies to increase chemosensitivity for MM treatment

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