Mannose and Phosphomannose Isomerase Regulate Energy Metabolism Under Glucose Starvation in Leukemia

Overview

Journal Cancer Sci

Specialty Oncology

Date 2021 Sep 17

PMID 34533861

Citations 14

Authors

Yusuke Saito

Mariko Kinoshita

Ai Yamada

Sayaka Kawano

Hong-Shan Liu

Sachiyo Kamimura

Midori Nakagawa

Syun Nagasawa

Tadao Taguchi

Shuhei Yamada

Hiroshi Moritake

Affiliations

Soon will be listed here.

Abstract

Diverse metabolic changes are induced by various driver oncogenes during the onset and progression of leukemia. By upregulating glycolysis, cancer cells acquire a proliferative advantage over normal hematopoietic cells; in addition, these changes in energy metabolism contribute to anticancer drug resistance. Because leukemia cells proliferate by consuming glucose as an energy source, an alternative nutrient source is essential when glucose levels in bone marrow are insufficient. We profiled sugar metabolism in leukemia cells and found that mannose is an energy source for glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway. Leukemia cells express high levels of phosphomannose isomerase (PMI), which mobilizes mannose to glycolysis; consequently, even mannose in the blood can be used as an energy source for glycolysis. Conversely, suppression of PMI expression or a mannose load exceeding the processing capacity of PMI inhibited transcription of genes related to mitochondrial metabolism and the TCA cycle, therefore suppressing the growth of leukemia cells. High PMI expression was also a poor prognostic factor for acute myeloid leukemia. Our findings reveal a new mechanism for glucose starvation resistance in leukemia. Furthermore, the combination of PMI suppression and mannose loading has potential as a novel treatment for driver oncogene-independent leukemia.

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References

Gautam L, Sharma R, Shrivastava P, Vyas S, Vyas S . Development and Characterization of Biocompatible Mannose Functionalized Mesospheres: an Effective Chemotherapeutic Approach for Lung Cancer Targeting. AAPS PharmSciTech. 2020; 21(5):190. DOI: 10.1208/s12249-020-01742-9. View

Roberts K, Mullighan C . Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nat Rev Clin Oncol. 2015; 12(6):344-57. DOI: 10.1038/nrclinonc.2015.38. View

Liu F, Xu X, Li C, Li C, Li Y, Yin S . Mannose synergizes with chemoradiotherapy to cure cancer via metabolically targeting HIF-1 in a novel triple-negative glioblastoma mouse model. Clin Transl Med. 2020; 10(7):e226. PMC: 7648968. DOI: 10.1002/ctm2.226. View

Somervaille T, Cleary M . Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006; 10(4):257-68. DOI: 10.1016/j.ccr.2006.08.020. View

Zhang D, Chia C, Jiao X, Jin W, Kasagi S, Wu R . D-mannose induces regulatory T cells and suppresses immunopathology. Nat Med. 2017; 23(9):1036-1045. DOI: 10.1038/nm.4375. View

Chen W, Wang Y, Zhao A, Xia L, Xie G, Su M . Enhanced Fructose Utilization Mediated by SLC2A5 Is a Unique Metabolic Feature of Acute Myeloid Leukemia with Therapeutic Potential. Cancer Cell. 2016; 30(5):779-791. PMC: 5496656. DOI: 10.1016/j.ccell.2016.09.006. View

Fang Z, Wang R, Zhao H, Yao H, Ouyang J, Zhang X . Mannose Promotes Metabolic Discrimination of Osteosarcoma Cells at Single-Cell Level by Mass Spectrometry. Anal Chem. 2020; 92(3):2690-2696. DOI: 10.1021/acs.analchem.9b04773. View

Saito Y, Nakahata S, Yamakawa N, Kaneda K, Ichihara E, Suekane A . CD52 as a molecular target for immunotherapy to treat acute myeloid leukemia with high EVI1 expression. Leukemia. 2011; 25(6):921-31. DOI: 10.1038/leu.2011.36. View

Warburg O . On respiratory impairment in cancer cells. Science. 1956; 124(3215):269-70. View

10.

Gonzalez P, OPrey J, Cardaci S, Barthet V, Sakamaki J, Beaumatin F . Mannose impairs tumour growth and enhances chemotherapy. Nature. 2018; 563(7733):719-723. DOI: 10.1038/s41586-018-0729-3. View

11.

Krause N, Wegner A . Fructose Metabolism in Cancer. Cells. 2020; 9(12). PMC: 7762580. DOI: 10.3390/cells9122635. View

12.

Tiziani S, Kang Y, Harjanto R, Axelrod J, Piermarocchi C, Roberts W . Metabolomics of the tumor microenvironment in pediatric acute lymphoblastic leukemia. PLoS One. 2013; 8(12):e82859. PMC: 3862732. DOI: 10.1371/journal.pone.0082859. View

13.

Miwa I, Taguchi T . A simple HPLC assay for plasma D-mannose. Clin Chim Acta. 2013; 422:42-3. DOI: 10.1016/j.cca.2013.04.005. View

14.

Lagadinou E, Sach A, Callahan K, Rossi R, Neering S, Minhajuddin M . BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013; 12(3):329-41. PMC: 3595363. DOI: 10.1016/j.stem.2012.12.013. View

15.

Saito Y, Chapple R, Lin A, Kitano A, Nakada D . AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow. Cell Stem Cell. 2015; 17(5):585-96. PMC: 4597792. DOI: 10.1016/j.stem.2015.08.019. View

16.

Saito Y, Kinoshita M, Yamada A, Kawano S, Liu H, Kamimura S . Mannose and phosphomannose isomerase regulate energy metabolism under glucose starvation in leukemia. Cancer Sci. 2021; 112(12):4944-4956. PMC: 8645730. DOI: 10.1111/cas.15138. View

17.

Wang Y, Israelsen W, Lee D, Yu V, Jeanson N, Clish C . Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell. 2014; 158(6):1309-1323. PMC: 4197056. DOI: 10.1016/j.cell.2014.07.048. View

18.

Jeong S, Savino A, Chirayil R, Barin E, Cheng Y, Park S . High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells. Cell Metab. 2020; 33(1):145-159.e6. PMC: 8168776. DOI: 10.1016/j.cmet.2020.12.005. View

19.

Osthus R, Shim H, Kim S, Li Q, Reddy R, Mukherjee M . Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000; 275(29):21797-800. DOI: 10.1074/jbc.C000023200. View

20.

Farge T, Saland E, De Toni F, Aroua N, Hosseini M, Perry R . Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism. Cancer Discov. 2017; 7(7):716-735. PMC: 5501738. DOI: 10.1158/2159-8290.CD-16-0441. View