PMID- 34571936
OWN - NLM
STAT- MEDLINE
DCOM- 20211115
LR  - 20211115
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 9
DP  - 2021 Sep 2
TI  - Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma 
      Cells by Promoting Glutathione Degradation.
LID - 10.3390/cells10092287 [doi]
LID - 2287
AB  - 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-kappaB, 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.
FAU - Chen, Jing
AU  - Chen J
AD  - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty 
      of Science, Utrecht University, 3508 TB Utrecht, The Netherlands.
FAU - Zaal, Esther A
AU  - Zaal EA
AD  - Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular 
      Research, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3508 
      TB Utrecht, The Netherlands.
AD  - Division of Cell Biology, Cancer & Metabolism, Department of Biomolecular Health 
      Sciences, Faculty of Veterinary Medicine, Utrecht University, 3508 TD Utrecht, 
      The Netherlands.
FAU - Berkers, Celia R
AU  - Berkers CR
AD  - Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular 
      Research, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3508 
      TB Utrecht, The Netherlands.
AD  - Division of Cell Biology, Cancer & Metabolism, Department of Biomolecular Health 
      Sciences, Faculty of Veterinary Medicine, Utrecht University, 3508 TD Utrecht, 
      The Netherlands.
FAU - Ruijtenbeek, Rob
AU  - Ruijtenbeek R
AD  - Pamgene International, 5200 BJ 's-Hertogenbosch, The Netherlands.
FAU - Garssen, Johan
AU  - Garssen J
AUID- ORCID: 0000-0002-8678-9182
AD  - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty 
      of Science, Utrecht University, 3508 TB Utrecht, The Netherlands.
AD  - Nutricia Research, 3508 TC Utrecht, The Netherlands.
FAU - Redegeld, Frank A
AU  - Redegeld FA
AUID- ORCID: 0000-0001-8830-7960
AD  - Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty 
      of Science, Utrecht University, 3508 TB Utrecht, The Netherlands.
LA  - eng
GR  - 201506180025/Chinese Scholarship Council/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210902
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 25167-62-8 (Docosahexaenoic Acids)
RN  - 69G8BD63PP (Bortezomib)
RN  - AAN7QOV9EA (Eicosapentaenoic Acid)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Biomarkers, Tumor/genetics/*metabolism
MH  - Bortezomib/*pharmacology
MH  - Docosahexaenoic Acids/*pharmacology
MH  - Eicosapentaenoic Acid/*pharmacology
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Glutathione/*metabolism
MH  - Humans
MH  - Multiple Myeloma/*drug therapy/metabolism/pathology
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
PMC - PMC8465636
OTO - NOTNLM
OT  - DHA
OT  - EPA
OT  - bortezomib
OT  - drug resistance
OT  - metabolome
OT  - multiple myeloma
OT  - omega-3 fatty acids
OT  - transcriptome
COIS- The authors declare that no conflicts of interest.
EDAT- 2021/09/29 06:00
MHDA- 2021/11/16 06:00
PMCR- 2021/09/02
CRDT- 2021/09/28 01:04
PHST- 2021/07/16 00:00 [received]
PHST- 2021/08/26 00:00 [revised]
PHST- 2021/08/31 00:00 [accepted]
PHST- 2021/09/28 01:04 [entrez]
PHST- 2021/09/29 06:00 [pubmed]
PHST- 2021/11/16 06:00 [medline]
PHST- 2021/09/02 00:00 [pmc-release]
AID - cells10092287 [pii]
AID - cells-10-02287 [pii]
AID - 10.3390/cells10092287 [doi]
PST - epublish
SO  - Cells. 2021 Sep 2;10(9):2287. doi: 10.3390/cells10092287.