Bortezomib resistance in multiple myeloma is associated with increased serine synthesis

Background The proteasome inhibitor bortezomib (BTZ) is successfully applied in the treatment of multiple myeloma, but its efficacy is restricted by the wide-spread occurrence of resistance. Metabolic alterations play an important role in cancer development and aid in the cellular adaptation to phar...

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Bibliographic Details
Published in:Cancer & metabolism Vol. 5; no. 1; pp. 7 - 12
Main Authors: Zaal, Esther A., Wu, Wei, Jansen, Gerrit, Zweegman, Sonja, Cloos, Jacqueline, Berkers, Celia R.
Format: Journal Article
Language:English
Published: London BioMed Central 29.08.2017
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
Apoptosis
Biomedical and Life Sciences
Biomedicine
Biosynthesis
Bortezomib
Breast cancer
Cancer Research
Cancer therapies
Carbon
Cell Biology
Cell growth
Dehydrogenases
Drug resistance
Drug therapy
Experiments
Imaging
Inhibitor drugs
Mass spectrometry
Melanoma
Metabolic Diseases
Metabolism
Metabolomics
Multiple myeloma
Mutation
Oncology
Patient outcomes
Penicillin
PHGDH
Proteins
Radiology
Scientific imaging
Targeted cancer therapy
Testing
PHGDH
Bortezomib
Metabolism
Drug resistance
Multiple myeloma
ISSN:2049-3002, 2049-3002
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Summary:Background The proteasome inhibitor bortezomib (BTZ) is successfully applied in the treatment of multiple myeloma, but its efficacy is restricted by the wide-spread occurrence of resistance. Metabolic alterations play an important role in cancer development and aid in the cellular adaptation to pharmacologically changed environments. Metabolic changes could therefore play an essential role in the development of drug resistance. However, specific metabolic pathways that can be targeted to improve bortezomib therapy remain unidentified. Methods We elucidated the metabolic mechanisms underlying bortezomib resistance by using mass spectrometry-based metabolomics and proteomics on BTZ-sensitive and BTZ–resistant multiple myeloma cell lines as well as in a set of CD138+ cells obtained from multiple myeloma patients. Results Our findings demonstrate that a rewired glucose metabolism sustains bortezomib resistance. Mechanistically, this results in higher activity of both the pentose phosphate pathway and serine synthesis pathway, ultimately leading to an increased anti-oxidant capacity of BTZ-resistant cells. Moreover, our results link both serine synthesis pathway activity and expression of 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of serine synthesis, to bortezomib resistance across different BTZ-resistant multiple myeloma cell lines. Consistently, serine starvation enhanced the cytotoxicity of bortezomib, underscoring the importance of serine metabolism in the response to BTZ. Importantly, in CD138+ cells of clinically bortezomib refractory multiple myeloma patients, PHGDH expression was also markedly increased. Conclusions Our findings indicate that interfering with serine metabolism may be a novel strategy to improve bortezomib therapy and identify PHGDH as a potential biomarker for BTZ resistance.
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ISSN:2049-3002
2049-3002
DOI:10.1186/s40170-017-0169-9