ArticleOncotarget2016
Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 48 citations in OpenAlex.
- An integrative approach to studying sphingolipid metabolism reveals p53 as a master regulator of the pathway.Journal of lipid research · 2026Article
- Activation of TP53 target genes in the primary response of triple-negative breast cancer cells to doxorubicin treatment.Scientific reports · 2025Article
- Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A.The EMBO journal · 2025Article
- Ceramide signaling in immunity: a molecular perspective.Lipids in health and disease · 2025Review
- Sphingolipid metabolism dysregulation: A cause for lung cancer development, progression, and resistance to therapies.Chinese medical journal pulmonary and critical care medicine · 2025Review
- Ceramides are fuel gauges on the drive to cardiometabolic disease.Physiological reviews · 2024Review
- The role of ACER2 in intestinal sphingolipid metabolism and gastrointestinal cancers.Frontiers in immunology · 2024Review
- A Near-Infrared Fluorogenic Probe for Rapid, Specific, and Ultrasensitive Detection of Sphingosine in Living Cells and In Vivo.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation.International journal of molecular sciences · 2023Article
- Mysterious sphingolipids: metabolic interrelationships at the center of pathophysiology.Frontiers in physiology · 2023Review
- ACER2 forms a cold tumor microenvironment and predicts the molecular subtype in bladder cancer: Results from real-world cohorts.Frontiers in genetics · 2023Article
- Potential Drug Targets for Ceramide Metabolism in Cardiovascular Disease.Journal of cardiovascular development and disease · 2022Review
- Review
- Manifold Roles of Ceramide Metabolism in Non-Alcoholic Fatty Liver Disease and Liver Cancer.Advances in experimental medicine and biology · 2022Article
- A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis.International journal of molecular sciences · 2021Review
- Acid ceramidase controls apoptosis and increases autophagy in human melanoma cells treated with doxorubicin.Scientific reports · 2021Article
- Dysregulation of lysophospholipid signaling by p53 in malignant cells and the tumor microenvironment.Cellular signalling · 2021Review
- A Genome-Wide Association Study Identifies Novel Risk Loci for Sarcopenia in a Taiwanese Population.Journal of inflammation research · 2021Article
- Design, Synthesis, and Biological Evaluation of a Series of Oxazolone Carboxamides as a Novel Class of Acid Ceramidase Inhibitors.Journal of medicinal chemistry · 2020Article
- Maternal and fetal alkaline ceramidase 2 is required for placental vascular integrity in mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Human cells respond to DNA damage by elevating sphingosine, a bioactive sphingolipid that induces programmed cell death (PCD) in response to various forms of stress, but its regulation and role in the DNA damage response remain obscure. Herein we demonstrate that DNA damage increases sphingosine levels in tumor cells by upregulating alkaline ceramidase 2 (ACER2) and that the upregulation of the ACER2/sphingosine pathway induces PCD in response to DNA damage by increasing the production of reactive oxygen species (ROS). Treatment with the DNA damaging agent doxorubicin increased both ACER2 expression and sphingosine levels in HCT116 cells in a dose-dependent manner. ACER2 overexpression increased sphingosine in HeLa cells whereas knocking down ACER2 inhibited the doxorubicin-induced increase in sphingosine in HCT116 cells, suggesting that DNA damage elevates sphingosine by upregulating ACER2. Knocking down ACER2 inhibited an increase in the apoptotic and necrotic cell population and the cleavage of poly ADP ribose polymerase (PARP) in HCT116 cells in response to doxorubicin as well as doxorubicin-induced release of lactate dehydrogenase (LDH) from these cells. Similar to treatment with doxorubicin, ACER2 overexpression induced an increase in the apoptotic and necrotic cell population and PARP cleavage in HeLa cells and LDH release from cells, suggesting that ACER2 upregulation mediates PCD in response to DNA damage through sphingosine. Mechanistic studies demonstrated that the upregulation of the ACER2/sphingosine pathway induces PCD by increasing ROS levels. Taken together, these results suggest that the ACER2/sphingosine pathway mediates PCD in response to DNA damage through ROS production.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.