Abstract

BackgroundThe 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.MethodsWe 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.ResultsOur 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.ConclusionsOur 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.

Highlights

  • 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

  • Bortezomib resistance in MM cells is not solely driven by adaptation of the proteasome itself To study BTZ resistance, we compared human BTZsensitive RPMI-8226 wild-type (WT) MM cells with two BTZ-resistant cell lines (BTZ/7 and BTZ/100), which grow in the presence of 7 and 100 nM BTZ, respectively

  • Bortezomib resistance correlates to the expression of phosphoglycerate dehydrogenase (PHGDH) Having established the importance of both the phosphate pathway (PPP) and synthesis pathway (SSP) in the response of cells to BTZ, we asked whether these differences were found on the protein level

Read more

Summary

Introduction

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 play an essential role in the development of drug resistance. The proteasome inhibitor bortezomib (BTZ) is widely used in the treatment of multiple myeloma (MM) [1, 2]. The 20S core particle consists of two outer rings of α-subunits and two inner rings of β-subunits. Three of these β-subunits, termed β1, β2, and β5 are catalytically active [3]. Resistance is associated with mutations in the binding pocket of the β5 subunit (PSMB5), resulting in impaired binding of the drug [10,11,12], upregulation of the proteasomal

Objectives
Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call