pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma
| Autor: | Brandon J. Koch, Philip D. Benson, Sam Kiousis, Amy E. Lee, Ajal M. Dave, Elsa Varughese, Michael D. Monterey, Saroj P. Mathupala, Andrew E. Sloan, James P. Caruso |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Gene isoform Monocarboxylic Acid Transporters Cancer Research Original article Transcription Genetic Gene Expression lcsh:RC254-282 ACCA α-cyano-4-hydroxycinnamic acid PBS Dulbecco's phosphate buffered saline 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Genes Reporter Glioma Cell Line Tumor medicine Humans Glycolysis Lactic Acid Hypoxia Promoter Regions Genetic Cells Cultured ds double stranded Monocarboxylate transporter Tumor microenvironment biology Hypoxia (medical) Hydrogen-Ion Concentration GBM glioblastoma multiforme lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease MCS multicloning site Cell Hypoxia Lactic acid Gene Expression Regulation Neoplastic 030104 developmental biology Biochemistry chemistry Anaerobic glycolysis 030220 oncology & carcinogenesis Astrocytes Mutation biology.protein medicine.symptom Transcription Initiation Site Glioblastoma |
| Zdroj: | Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 19, Iss 2, Pp 121-134 (2017) |
| ISSN: | 1476-5586 |
| Popis: | Highly malignant brain tumors harbor the aberrant propensity for aerobic glycolysis, the excessive conversion of glucose to lactic acid even in the presence of ample tissue oxygen. Lactic acid is rapidly effluxed to the tumor microenvironment via a group of plasma-membrane transporters denoted monocarboxylate transporters (MCTs) to prevent "self-poisoning." One isoform, MCT2, has the highest affinity for lactate and thus should have the ability to respond to microenvironment conditions such as hypoxia, lactate, and pH to help maintain high glycolytic flux in the tumor. Yet, MCT2 is considered to not respond to hypoxia, which is counterintuitive. Its response to tumor lactate has not been reported. In this report, we experimentally identify the transcription initiation site/s for MCT2 in astrocytes (normal) and glioma (tumor). We then use a BACmid library to isolate a 4.2-kbp MCT2 promoter-exon I region and examine promoter response to glycolysis-mediated stimuli in glioma cells. Reporter analysis of nested-promoter constructs indicated response of MCT2 to hypoxia, pH, lactate, and glucose, the major physiological "players" that facilitate a tumor's growth and proliferation. Immunoblot analysis of native MCT2 expression under altered pH and hypoxia reflected the reporter data. The pH-mediated gene-regulation studies we describe are the first to record H + -based reporter studies for any mammalian system and demonstrate the exquisite response of the MCT2 gene to minute changes in tumor pH. Identical promoter usage also provides the first evidence of astrocytes harnessing the same gene regulatory regions to facilitate astrocyte-neuron lactate shuttling, a metabolic feature of normal brain. |
| Databáze: | OpenAIRE |
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