PMID- 35565432 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 14 IP - 9 DP - 2022 May 6 TI - LDH-A-Modulation and the Variability of LDH Isoenzyme Profiles in Murine Gliomas: A Link with Metabolic and Growth Responses. LID - 10.3390/cancers14092303 [doi] LID - 2303 AB - Three murine glioma cell lines (GL261, CT2A, and ALTS1C1) were modified to downregulate the expression of the murine LDH-A gene using shRNA, and compared to shRNA scrambled control (NC) cell lines. Differences in the expression of LDH-A and LDH-B mRNA, protein and enzymatic activity, as well as their LDH isoenzyme profiles, were observed in the six cell lines, and confirmed successful LDH-A KD. LDH-A KD (knock-down) resulted in metabolic changes in cells with a reduction in glycolysis (GlycoPER) and an increase in basal respiratory rate (mitoOCR). GL261 cells had a more limited ATP production capacity compared to CT2A and ALTS1C1 cells. An analysis of mRNA expression data indicated that: (i) GL261 LDH-A KD cells may have an improved ability to metabolize lactate into the TCA cycle; and (ii) that GL261 LDH-A KD cells can upregulate lipid metabolism/fatty acid oxidation pathways, whereas the other glioma cell lines do not have this capacity. These two observations suggest that GL261 LDH-A KD cells can develop/activate alternative metabolic pathways for enhanced survival in a nutrient-limited environment, and that specific nutrient limitations have a variable impact on tumor cell metabolism and proliferation. The phenotypic effects of LDH-A KD were compared to those in control (NC) cells and tumors. LDH-A KD prolonged the doubling time of GL261 cells in culture and prevented the formation of subcutaneous flank tumors in immune-competent C57BL/6 mice, whereas GL261 NC tumors had a prolonged growth delay in C57BL/6 mice. In nude mice, both LDH-A KD and NC GL261 tumors grew rapidly (more rapidly than GL261 NC tumors in C57BL/6 mice), demonstrating the impact of an intact immune system on GL261 tumor growth. No differences between NC and KD cell proliferation (in vitro) or tumor growth in C57BL/6 mice (doubling time) were observed for CT2A and ALTS1C1 cells and tumors, despite the small changes to their LDH isoenzyme profiles. These results suggest that GL261 glioma cells (but not CT2A and ALTS1C1 cells) are pre-programmed to have the capacity for activating different metabolic pathways with higher TCA cycle activity, and that this capacity is enhanced by LDH-A depletion. We observed that the combined impact of LDH-A depletion and the immune system had a significant impact on the growth of subcutaneous-located GL261 tumors. FAU - Shindo, Masahiro AU - Shindo M AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Neurosurgery, Nozaki Tokushukai Hospital, Osaka 5740074, Japan. FAU - Maeda, Masatomo AU - Maeda M AUID- ORCID: 0000-0002-5825-5378 AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Neurosurgery, Nozaki Tokushukai Hospital, Osaka 5740074, Japan. FAU - Myat, Ko AU - Myat K AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Mane, Mayuresh M AU - Mane MM AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Cohen, Ivan J AU - Cohen IJ AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. FAU - Vemuri, Kiranmayi AU - Vemuri K AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Genetics, Rutgers University, New Brunswick, NJ 08901, USA. FAU - Albeg, Avi S AU - Albeg AS AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Serganova, Inna AU - Serganova I AUID- ORCID: 0000-0003-3561-8663 AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10021, USA. FAU - Blasberg, Ronald AU - Blasberg R AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 52, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. LA - eng GR - R01 CA163980/CA/NCI NIH HHS/United States GR - R50 CA221810/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R01 CA204924/CA/NCI NIH HHS/United States GR - R01 CA215136/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20220506 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC9100845 OTO - NOTNLM OT - LDH isoenzymes OT - LDH-A and LDH-B immunohistochemistry OT - LDH-A shRNA knock-down OT - glioblastoma OT - immune-competent and incompetent host animals OT - tumor growth COIS- The authors declare no conflict of interest. EDAT- 2022/05/15 06:00 MHDA- 2022/05/15 06:01 PMCR- 2022/05/06 CRDT- 2022/05/14 01:18 PHST- 2021/12/04 00:00 [received] PHST- 2022/04/11 00:00 [revised] PHST- 2022/04/28 00:00 [accepted] PHST- 2022/05/14 01:18 [entrez] PHST- 2022/05/15 06:00 [pubmed] PHST- 2022/05/15 06:01 [medline] PHST- 2022/05/06 00:00 [pmc-release] AID - cancers14092303 [pii] AID - cancers-14-02303 [pii] AID - 10.3390/cancers14092303 [doi] PST - epublish SO - Cancers (Basel). 2022 May 6;14(9):2303. doi: 10.3390/cancers14092303.