Metabolome-Wide Reprogramming Modulated by Wnt/β-Catenin Signaling Pathway
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
A family of signal transduction pathways known as wingless type (Wnt) signaling pathways is essential to developmental processes like cell division and proliferation. Mutation in Wnt signaling results in a variety of diseases, including cancers of the breast, colon, and skin, metabolic disease, and neurodegenerative disease; thus, the Wnt signaling pathways have been attractive targets for disease treatment. However, the complicatedness and large involveness of the pathway often hampers pinpointing the specific targets of the metabolic process. In our current study, we investigated the differential metabolic regulation by the overexpression of the Wnt signaling pathway in a timely-resolved manner by applying high-throughput and un-targeted metabolite profiling. We have detected and annotated 321 metabolite peaks from a total of 36 human embryonic kidney (HEK) 293 cells using GC-TOF MS and LC-Orbitrap MS. The un-targeted metabolomic analysis identified the radical reprogramming of a range of central carbon/nitrogen metabolism pathways, including glycolysis, TCA cycle, and glutaminolysis, and fatty acid pathways. The investigation, combined with targeted mRNA profiles, elucidated an explicit understanding of activated fatty acid metabolism (β-oxidation and biosynthesis). The findings proposed detailed mechanistic biochemical dynamics in response to Wnt-driven metabolic changes, which may help design precise therapeutic targets for Wnt-related diseases.
Abstract
A family of signal transduction pathways known as wingless type (Wnt) signaling pathways is essential to developmental processes like cell division and proliferation. Mutation in Wnt signaling results in a variety of diseases, including cancers of the breast, colon, and skin, metabolic disease, and neurodegenerative disease; thus, the Wnt signaling pathways have been attractive targets for disease treatment. However, the complicatedness and large involveness of the pathway often hampers pinpointing the specific targets of the metabolic process. In our current study, we investigated the differential metabolic regulation by the overexpression of the Wnt signaling pathway in a timely-resolved manner by applying high-throughput and un-targeted metabolite profiling. We have detected and annotated 321 metabolite peaks from a total of 36 human embryonic kidney (HEK) 293 cells using GC-TOF MS and LC-Orbitrap MS. The un-targeted metabolomic analysis identified the radical reprogramming of a range of central carbon/nitrogen metabolism pathways, including glycolysis, TCA cycle, and glutaminolysis, and fatty acid pathways. The investigation, combined with targeted mRNA profiles, elucidated an explicit understanding of activated fatty acid metabolism (β-oxidation and biosynthesis). The findings proposed detailed mechanistic biochemical dynamics in response to Wnt-driven metabolic changes, which may help design precise therapeutic targets for Wnt-related diseases.
참고문헌 (37)
- Komiya Y, "Wnt signal transduction pathways", Organogenesis, 4, pp.68~75 (2008)
- Wodarz A, "Mechanisms of Wnt signaling in development", Ann. Rev. Cell Deve. Biol, 14, pp.59~88 (1998)
- Aberle H, "β-catenin is a target for the ubiquitin–proteasome pathway", EMBO J, 16, pp.3797~3804 (1997)
- Baarsma HA, "The WNT signaling pathway from ligand secretion to gene transcription: molecular mechanisms and pharmacological targets", Pharmacol. Ther, 138, pp.66~83 (2013)
- Ng LF, "WNT signaling in disease", Cells, 8, pp.826~ (2019)
- Kahn M, "Can we safely target the WNT pathway?", Nat. Rev. Drug Discov, 13, pp.513~532 (2014)
- MacDonald BT, "Wnt", β-catenin signaling: components, mechanisms, and diseases, 2009, pp.17, 9~26
- 정연상, "Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex", Experimental and Molecular Medicine, 52, pp.1~9 (2020), 생화학분자생물학회[DOI]
- Bastakoty D, "Wnt", β‐catenin pathway in tissue injury: roles in pathology and therapeutic opportunities for regeneration, 2016, pp.30, 3271~3284
- Son Y, "Ilimaquinone inhibits neovascular age-related macular degeneration through modulation of Wnt", β-catenin and p53 pathways, 2020, pp.161, 105146~
- Song Geu Rim, "Root Bark of Morus alba L. and Its Bioactive Ingredient, Ursolic Acid, Suppress the Proliferation of Multiple Myeloma Cells by Inhibiting Wnt", β-Catenin Pathway, 2021, pp.31(11), 1559~1567[DOI]
- Park S, "Hexachlorophene inhibits Wnt", β-catenin pathway by promoting Siahmediated β-catenin degradation, 2006, pp.70, 960~966
- Arikawa E, "RT2 Profiler PCR Arrays: Pathway-focused gene expression profiling with qRT-PCR", SA Biosci. Technical Article, 11~ (2010)
- Adebo OA, "Application of gas chromatography–mass spectrometry (GC‐MS)‐based metabolomics for the study of fermented cereal and legume foods: A review", Int. J. Food Sci. Technol, 56, pp.1514~1534 (2021)
- Park SJ, "Disease type-and status-specific alteration of CSF metabolome coordinated with clinical parameters in inflammatory demyelinating diseases of CNS", PLoS One, 11, pp.e0166277~ (2016)
- Kind T, "FiehnLib: mass spectral and retention index libraries for metabolomics based on quadrupole and time-of-flight gas chromatography", mass spectrometry, 2009, pp.81, 10038~10048
- Park SJ, "Exposure of ultrafine particulate matter causes glutathione redox imbalance in the hippocampus: A neurometabolic susceptibility to Alzheimer's pathology", Sci. Total Environ, 718, pp.137267~ (2020)
- Barupal DK, "Chemical Similarity Enrichment Analysis (ChemRICH) as alternative to biochemical pathway mapping for metabolomic datasets", Sci. Rep, 7, pp.14567~ (2017)
- Kuhn M, "STITCH: interaction networks of chemicals and proteins", Nucleic Acids Res, 36, pp.D684~D688 (2007)
- Reischmann P, "Measured effects of Wnt3a on proliferation of HEK293T cells depend on the applied assay", Int. J. Cell Biol, 2015, pp.928502~ (2015)
- Jia L, "Effects of Wnt proteins on cell proliferation and apoptosis in HEK293 cells", Cell Biol. Int, 32, pp.807~813 (2008)
- Oloumi A, "Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrinlinked kinase in mammalian cells", Oncogene, 25, pp.7747~7757 (2006)
- Gujral TS, "A system-wide investigation of the dynamics of Wnt signaling reveals novel phases of transcriptional regulation", PLoS One, 5, pp.e10024~ (2010)
- He S, "Wnt3a: functions and implications in cancer", Chinese J. Cancer, 34, pp.554~562 (2015)
- Sethi JK, "Wnt signalling and the control of cellular metabolism", Biochem. J, 427, pp.1~17 (2010)
- Vallée A, "The key role of the WNT", β-catenin pathway in metabolic reprogramming in cancers under normoxic conditions, 2021, pp.13, 5557~
- Zaugg K, "Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress", Genes Dev, 25, pp.1041~1051 (2011)
- Kühnl J, "Functional analysis of the methylmalonyl‐CoA epimerase from Caenorhabditis elegans", FEBS J, 272, pp.1465~1477 (2005)
- Qiu F, "Lower expression of SLC27A1 enhances intramuscular fat deposition in chicken via down-regulated fatty acid oxidation mediated by CPT1A", Front. Physiol, 8, pp.449~ (2017)
- Ma Y, "Long-chain fatty acyl-CoA synthetase 1 promotes prostate cancer progression by elevation of lipogenesis and fatty acid beta-oxidation", Oncogene, 40, pp.1806~1820 (2021)
- Zhao Z, "Effects of overexpression of ACSL1 gene on the synthesis of unsaturated fatty acids in adipocytes of bovine", Arch. Biochem. Biophys, 695, pp.108648~ (2020)
- Zhao Z, "Interference with ACSL1 gene in bovine adipocytes: Transcriptome profiling of circRNA related to unsaturated fatty acid production", Genomics, 113, pp.3967~3977 (2021)
- Lai KK, "Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6", Gastroenterology, 152, pp.1477~1491 (2017)
- Furuhashi M, "Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets", Nat. Rev. Drug Discov, 7, pp.489~503 (2008)
- Bensaad K, "Fatty acid uptake and lipid storage induced by HIF-1αcontribute to cell growth and survival after hypoxia-reoxygenation", Cell Rep, 9, pp.349~365 (2014)
- Nakamura MT, "Regulation of energy metabolism by long-chain fatty acids", Progress Lipid Res, 53, pp.124~144 (2014)
- Hosios AM, "The redox requirements of proliferating mammalian cells", J. Biol. Chem, 293, pp.7490~7498 (2018)