Mitochondrial metabolic determinants of multiple myeloma growth, survival, and therapy efficacy

Abstract

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the clonal proliferation of antibody producing plasma cells. Despite the use of next generation proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and immunotherapy, the development of therapy refractory disease is common, with approximately 20% of MM patients succumbing to aggressive treatment-refractory disease within 2 years of diagnosis. A large emphasis is placed on understanding inter/intra-tumoral genetic, epigenetic and transcriptomic changes contributing to relapsed/refractory disease, however, the contribution of cellular metabolism and intrinsic/extrinsic metabolites to therapy sensitivity and resistance mechanisms is less well understood. Cancer cells depend on specific metabolites for bioenergetics, duplication of biomass and redox homeostasis for growth, proliferation, and survival. Cancer therapy, importantly, largely relies on targeting cellular growth, proliferation, and survival. Thus, understanding the metabolic changes intersecting with a drug's mechanism of action can inform us of methods to elicit deeper responses and prevent acquired resistance. Knowledge of the Warburg effect and elevated aerobic glycolysis in cancer cells, including MM, has allowed us to capitalize on this phenomenon for diagnostics and prognostics. The demonstration that mitochondria play critical roles in cancer development, progression, and therapy sensitivity despite the inherent preference of cancer cells to engage aerobic glycolysis has re-invigorated deeper inquiry into how mitochondrial metabolism regulates tumor biology and therapy efficacy. Mitochondria are the sole source for coupled respiration mediated ATP synthesis and a key source for the anabolic synthesis of amino acids and reducing equivalents. Beyond their core metabolic activities, mitochondria facilitate apoptotic cell death, impact the activation of the cytosolic integrated response to stress, and through nuclear and cytosolic retrograde crosstalk maintain cell fitness and survival. Here, we hope to shed light on key mitochondrial functions that shape MM development and therapy sensitivity.

Keywords: B cell; metabolism; mitochondria; multiple myeloma; therapy.

Figure 1

Metabolic changes during B-cell differentiation. Metabolic states of naïve B cells, activated B cells, fully differentiated plasma cells and MM cells. Normal B-cells transition from a primary dependency on glycolysis to additionally relying on elevated oxidative phosphorylation during development and differentiation. Myeloma cells continue to rely on glycolysis driven in part by the hypoxic conditions in the bone marrow, increased bioenergetic demands to sustain rapid growth and proliferation with OXPHOS likely supporting cellular functions like antibody production. BLIMP1, B lymphocyte-induced maturation protein 1.

Figure 2

Multifaceted roles of the mitochondria.

Figure 3

Timeline of mitochondrial biology. Subset of major milestones and discoveries are shown. Nobel Prize-winning discoveries are highlighted in red.

Figure 4

Mitochondrial functions in a normal plasma vs multiple myeloma cell:(A) In normal plasma cells, glucose is primarily metabolized through glycolysis into pyruvate and acetyl-CoA. Acetyl-CoA enters the mitochondrial TCA cycle to produce a series of intermediates and reducing equivalents that are utilized by the ETC to generate ATP through OXPHOS; (B) Cancer cells generate energy preferentially by glycolysis even in the presence of oxygen, a phenomenon known as the “Warburg effect.” This metabolic switch towards “aerobic glycolysis” increases glucose uptake mediated via glucose transporter (GLUT) upregulation and oxidation of pyruvate to lactate. (C) Normal cells appropriately respond to stress by activating apoptosis; (D) Cancer cells overexpress anti-apoptotic proteins (BCL-2) to counteract pro-apoptotic BAX/BAK activation, allowing for the evasion of programmed cell death.

Figure 5

Mitochondrial therapeutic targets. Carbon metabolism (Krebs cycle and oxidative phosphorylation) and apoptosis pathways are shown, with inhibitors highlighted in red. Abbreviations: 2-hydroxyglutarate (2-HG); BCL-2 homologous antagonist killer (BAK); BCL-2-associated X protein (BAX); B-cell lymphoma 2 (BCL-2); BCL-2 homology domain 3 (BH3); glutaminase1 (GLS1); inhibitor of apoptosis (IAP); isocitrate dehydrogenase 2 (IDH2); alpha-ketoglutarate dehydrogenase (OGDH); pyruvate dehydrogenase complex (PDHc); second mitochondria-derived activator of caspases (SMAC).