Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

Abstract

Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhosDLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors. Cells adapt their metabolism to satisfy changing biosynthetic and bioenergetic needs.1,2 Investigation of metabolic reprogramming in cancer has provided insights into the metabolic control of proliferation and survival.3-5 Although the initial focus of this field has been aerobic glycolysis (the Warburg effect), 6 increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis, including varied contribution of mitochondria to tumor metabolism as well as heterogeneity in fuel utilization pathways. 7-12Diffuse large B-cell lymphomas (DLBCLs) are a genetically heterogeneous group of tumors that can be classified into distinct molecular subtypes based on gene expression profiles. The cell-of-origin (COO) classification defined DLBCL subsets that shared certain components of their RNA profiles with normal germinal center B cells (GCBs) or in vitroactivated B cells (ABCs), and a third undefined subset designated 'type 3'. 13 Using an independent approach, the consensus cluster classification (CCC) framework compared the transcriptional profiles of DLBCL groups with each other without referencing normal B cells. 14 CCC identified tumorintrinsic distinctions in three highly reproducible clusters; the B-cell receptor/proliferation cluster (BCR-DLBCL) showing increased expression of BCR signa...

Germinal center‐derived lymphomas: The darkest side of humoral immunity

“…192 usage from glycolysis to the PPP also represents a possible therapeutic option. 193,194 OxPhos-DLBCLs were reported to require mitochondrial palmitate oxidation to produce ATP, 193 or the mitochondrial translation machinery to raise ETC protein levels. 193,194 OxPhos-DLBCLs were reported to require mitochondrial palmitate oxidation to produce ATP, 193 or the mitochondrial translation machinery to raise ETC protein levels.…”

“…125 In addition, certain DLBCLs defined by gene expression profiling manifest addiction to glycolysis, while other "OxPhos-DLBCLs" depend on the electron transport chain (ETC) activity. 194 Inhibition of the mitochondrial fatty acid oxidation 193 or mitochondrial translation machinery 194 194 Inhibition of the mitochondrial fatty acid oxidation 193 or mitochondrial translation machinery 194 …”

“…125 In addition, certain DLBCLs defined by gene expression profiling manifest addiction to glycolysis, while other "OxPhos-DLBCLs" depend on the electron transport chain (ETC) activity. 193,194 OxPhos-DLBCLs were reported to require mitochondrial palmitate oxidation to produce ATP, 193 or the mitochondrial translation machinery to raise ETC protein levels. 194 Inhibition of the mitochondrial fatty acid oxidation 193 or mitochondrial translation machinery 194 We speculate that lymphoma B cells that have undergone metabolic rewiring are better fit than normal immune T cells in these conditions, and when combined with genetic lesions that favor antitumor immune escape (such as TNFRSF14 loss, CD70 gain, etc.)…”

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

“…Inhibiting the mitochondrial gene expression and translation pathway by TIG could induce MYC oncogene-dependent tumor cell death, including the osteosarcomas (Oran et al, 2016) and lymphomas (D’Andrea et al, 2016). As the mitochondrial energy metabolism provides distinct pro-survival benefits to diffuse large B-cell lymphomas (DLBCLs), pharmacological perturbation of the mitochondrial translation pathway with TIG is proved to be selectively toxic to DLBCL cell lines (Norberg et al, 2016). In addition, another group has identified that TIG could serve as a potential new therapeutic drug for treatment of retinoblastoma (RB1) -deficient breast cancer (Jones et al, 2016).…”

Antibiotic tigecycline inhibits cell proliferation, migration and invasion via down‐regulating CCNE2 in pancreatic ductal adenocarcinoma

“…Then, we found that tigecycline also plays important roles in various solid tumours, such as gastric cancer, oral squamous cell carcinoma (OSCC), malignant melanoma, neuroblastoma and glioma . Meanwhile, other groups also found that tigecycline acts as a promising anti‐cancer drug for many other kinds of cancers, including triple‐negative breast cancer (TNBC), diffuse large B‐cell lymphomas (DLBCLs), cervical squamous cell carcinoma, ovarian cancer, hepatocellular carcinoma, chronic myeloid leukaemia (CML), prostate cancer and lung cancer . Recently, c‐Abl–specific tyrosine kinase inhibitors (TKIs) in combination with tigecycline were shown to be a promising strategy to treat patients with CML .…”