Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex.

Autor: Astrinidis A; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Li C; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Zhang EY; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Zhao X; Clinical Mass Spectrometry Laboratory, Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Zhao S; Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Guo M; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.; Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Olatoke T; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Mattam U; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Huang R; Clinical Mass Spectrometry Laboratory, Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Zhang AG; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Pitstick L; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Kopras EJ; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Gupta N; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Jandarov R; Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Smith EP; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Fugate E; Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Lindquist D; Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Markiewski MM; Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, Texas, USA., Karbowniczek M; Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, Texas, USA., Wikenheiser-Brokamp KA; Division of Pathology and Laboratory Medicine; Division of Pulmonary Medicine; and Division of Pulmonary Biology, Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Setchell KDR; Clinical Mass Spectrometry Laboratory, Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., McCormack FX; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Xu Y; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.; Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA., Yu JJ; Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2023 May 08; Vol. 8 (9). Date of Electronic Publication: 2023 May 08.
DOI: 10.1172/jci.insight.166850
Abstrakt: Tuberous sclerosis complex (TSC) is characterized by multisystem, low-grade neoplasia involving the lung, kidneys, brain, and heart. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting almost exclusively women. TSC and LAM are both caused by mutations in TSC1 and TSC2 that result in mTORC1 hyperactivation. Here, we report that single-cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid biosynthesis pathway. Accordingly, the expression of acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzymes controlling sphingolipid and ceramide metabolism, was significantly increased in TSC2-null cells. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids, and suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) resulted in markedly decreased TSC2-null cell viability. In vivo, 17a significantly decreased the growth of TSC2-null cell-derived mouse xenografts and short-term lung colonization by TSC2-null cells. Combined rapamycin and 17a treatment synergistically inhibited renal cystadenoma growth in Tsc2+/- mice, consistent with increased ASAH1 expression and activity being rapamycin insensitive. Collectively, the present study identifies rapamycin-insensitive ASAH1 upregulation in TSC2-null cells and tumors and provides evidence that targeting aberrant sphingolipid biosynthesis pathways has potential therapeutic value in mechanistic target of rapamycin complex 1-hyperactive neoplasms, including TSC and LAM.
Databáze: MEDLINE