Metabolic Features of Multiple Myeloma

Abstract

Cancer is known for its cellular changes contributing to tumour growth and cell proliferation. As part of these changes, metabolic rearrangements are identified in several cancers, including multiple myeloma (MM), which is a condition whereby malignant plasma cells accumulate in the bone marrow (BM). These metabolic changes consist of generation, inhibition and accumulation of metabolites and metabolic shifts in MM cells. Changes in the BM micro-environment could be the reason for such adjustments. Enhancement of glycolysis and glutaminolysis is found in MM cells compared to healthy cells. Metabolites and enzymes can be upregulated or downregulated and play a crucial role in drug resistance. Therefore, this review will focus on changes in glucose and glutamine metabolism linked with the emergence of drug resistance. Moreover, metabolites do not only affect other metabolic components to benefit cancer development; they also interfere with transcription factors involved in proliferation and apoptotic regulation.

Keywords: bone marrow micro-environment; metabolism; multiple myeloma.

Figure 1

Schematic presentation of targets in glucose and glutamine metabolism in MM cells. Metabolic rearrangements in MM cells after administering compounds inducing stimulation or inhibition. 3BP enters the cell through MCT4 and inhibits HKII connected to the outer mitochondrial membrane via VDAC leading to ATP reduction and the loss of viable cells. 2DG enters the cell through GLUT and is phosphorylated by HKII. The phosphorylated form cannot be metabolised and accumulates by consequence leading to glycolysis blockage. Compound 20 inhibits GLUT4 resulting in chemosensitising. The inhibition of PDK on PDH is suppressed after addition of DCA to MM cells, which inhibits PDK. As a result, PDH activity increases and lactate production decreases, whereby TCA activity is increased. CHC is a MCT1 competitive inhibitor and blocks the entrance of lactate into the cell. This lack of fuel results in apoptosis due to ATP reduction. However, BMSC supply MM cells with lactate. Glutamine enters the cell through three transporters: ASCT2, LAT1 and SNAT1, with ASCT2 being the major glutamine transporter. Compound 968 inhibits GLS inducing MYC degradation and decrease of CD47 and PD-L1. MM cells lack GS, resulting in low intracellular glutamine concentrations and leading to higher glutamine influx. GPNA is a glutamine transporter inhibitor and induces a lack of glutamine intracellularly, which disadvantages AA synthesis and reduces mTORC1 activity, resulting in less cell proliferation. Instead of inhibiting glutamine transporters, l-asparaginase hydrolyses glutamine. AA, amino acid; BMSC, bone marrow stromal cells; 3BP, 3-bromopyruvate; CHC, α-cyano-4-hydroxycinnamic acid; DCA, dichloroacetate; 2DG, 2-deoxyglucose; 2-DG-6-P, 2-deoxyglucose-6-phosphate; G-6-P, glucose-6-phosphate; GLDH, glutamate dehydrogenase; GLS1, glutaminase 1; GLS2, glutaminase 2; GPNA, l-γ-glutamyl-p-nitroanilide; GS, glutamine synthetase; HKII, hexokinase II; LDH, lactate dehydrogenase; MM, multiple myeloma; MYC, myelocytomatosis oncogene cellular homolog; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PEP, phosphoenolpyruvate; PKM2, pyruvate kinase M2; ROS, reactive oxygen species; VDAC, voltage-dependent anion channel; , reduction; , strong reduction; , increase; , strong increase.