title: Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis.
abstract: Reelin is an extracellular matrix protein that is crucial for neuron migration, adhesion, and positioning. We examined the expression of Reelin in a large cohort of multiple myeloma patients recorded in Gene Expression Omnibus (GEO) database and used over-expression and siRNA knockdown of Reelin to investigate the role of Reelin in myeloma cell growth. We find that Reelin expression is negatively associated with myeloma prognosis. Reelin promotes myeloma cell proliferation in vitro as well as in vivo. The Warburg effect, evidenced by increased glucose uptake and lactate production, is also enhanced in Reelin-expressing cells. The activation of FAK/Syk/Akt/mTOR and STAT3 pathways contributes to Reelin-induced cancer cell growth and metabolic reprogramming. Our findings further reveal that activated Akt and STAT3 pathways induce the upregulation of HIF1α and its downstream targets (LDHA and PDK1), leading to increased glycolysis in myeloma cells. Together, our results demonstrate the critical contributions of Reelin to myeloma growth and metabolism. It presents an opportunity for myeloma therapeutic intervention by inhibiting Reelin and its signaling pathways.
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, 100191, China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Qin
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, 100191, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Lin
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, 100191, China.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, 100191, China.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, 100191, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Song
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, 100191, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hao
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, 100191, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Risheng
authors.initials: R
authors.lastname: Wei
authors.affiliation: Peking University Institute of Hematology, People's Hospital, Beijing, 100044, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Huang
authors.affiliation: Peking University Institute of Hematology, People's Hospital, Beijing, 100044, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, 100191, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ge
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D000091042:Reelin Protein; D019344:Lactic Acid; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005947:Glucose