title: Retinoic acid-induced differentiation increases the rate of oxygen consumption and enhances the spare respiratory capacity of mitochondria in SH-SY5Y cells.
abstract: Retinoic acid (RA) is used in differentiation therapy to treat a variety of cancers including neuroblastoma. The contributing factors for its therapeutic efficacy are poorly understood. However, mitochondria (MT) have been implicated as key effectors in RA-mediated differentiation process. Here we utilize the SH-SY5Y human neuroblastoma cell line as a model to examine how RA influences MT during the differentiation process. We find that RA confers an approximately sixfold increase in the oxygen consumption rate while the rate of glycolysis modestly increases. RA treatment does not increase the number of MT or cause measurable changes in the composition of the electron transport chain. Rather, RA treatment significantly increases the mitochondrial spare respiratory capacity. We propose a competition model for the therapeutic effects of RA. Specifically, the high metabolic rate in differentiated cells limits the availability of metabolic nutrients for use by the undifferentiated cells and suppresses their growth. Thus, RA treatment provides a selective advantage for the differentiated state.
authors.affiliation: Lawrence Berkeley National Laboratory, Life Sciences Division, 1 Cyclotron Rd., Berkeley, CA 94720, USA.
authors.forename: Zhiyin
authors.initials: Z
authors.lastname: Xun
authors.forename: Do-Yup
authors.initials: DY
authors.lastname: Lee
authors.forename: James
authors.initials: J
authors.lastname: Lim
authors.forename: Christie A
authors.initials: CA
authors.lastname: Canaria
authors.forename: Adam
authors.initials: A
authors.lastname: Barnebey
authors.forename: Steven M
authors.initials: SM
authors.lastname: Yanonne
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects*; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D045222:Electron Transport Chain Complex Proteins; D014212:Tretinoin