title: 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 OxPhos-DLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Erik
authors: E
authors: Norberg
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Ana
authors: A
authors: Lako
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Pei-Hsuan
authors: PH
authors: Chen
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Illana A
authors: IA
authors: Stanley
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Feng
authors: F
authors: Zhou
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Scott B
authors: SB
authors: Ficarro
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Bjoern
authors: B
authors: Chapuy
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Linfeng
authors: L
authors: Chen
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Scott
authors: S
authors: Rodig
authors: Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea.
authors: Donghyuk
authors: D
authors: Shin
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Dong Wook
authors: DW
authors: Choi
authors: Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea.
authors: Sangho
authors: S
authors: Lee
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Margaret A
authors: MA
authors: Shipp
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Jarrod A
authors: JA
authors: Marto
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Nika N
authors: NN
authors: Danial
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D020816:Amino Acid Motifs; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D020653:Peptide Elongation Factor G / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010444:Peptide Elongation Factor Tu / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D045222:Electron Transport Chain Complex Proteins; C441680:GFM1 protein, human; C000604470:MRPS7 protein, human; D024101:Mitochondrial Proteins; D020653:Peptide Elongation Factor G; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011947:Receptors, Antigen, B-Cell; D012269:Ribosomal Proteins; C091648:TUFM protein, human; D010444:Peptide Elongation Factor Tu; D000111:Acetylcysteine