ArticleThe Journal of biological chemistry2010
Alkaline ceramidase 2 (ACER2) and its product dihydrosphingosine mediate the cytotoxicity of N-(4-hydroxyphenyl)retinamide in tumor cells.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 49 citations in OpenAlex.
- The bioactive sphingolipid playbook. A primer for the uninitiated as well as sphingolipidologists.Journal of lipid research · 2025Review
- The role of ACER2 in intestinal sphingolipid metabolism and gastrointestinal cancers.Frontiers in immunology · 2024Review
- Molecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Naxitamab Activity in Neuroblastoma Cells Is Enhanced by Nanofenretinide and Nanospermidine.Pharmaceutics · 2023Article
- The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response.International journal of molecular sciences · 2023Review
- Sphingolipids in Lung Pathology in the Coronavirus Disease Era: A Review of Sphingolipid Involvement in the Pathogenesis of Lung Damage.Frontiers in physiology · 2021Review
- A Genome-Wide Association Study Identifies Novel Risk Loci for Sarcopenia in a Taiwanese Population.Journal of inflammation research · 2021Article
- TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer.Cell death & disease · 2020Article
- Review
- Human alkaline ceramidase 2 promotes the growth, invasion, and migration of hepatocellular carcinoma cells via sphingomyelin phosphodiesterase acid-like 3B.Cancer science · 2020Article
- Clinical application of ceramide in cancer treatment.Breast cancer (Tokyo, Japan) · 2019Review
- New fluorogenic probes for neutral and alkaline ceramidases.Journal of lipid research · 2019Article
- Probing de novo sphingolipid metabolism in mammalian cells utilizing mass spectrometry.Journal of lipid research · 2018Article
- Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2.Cell death and differentiation · 2018Article
- Sphingolipid metabolism in cancer signalling and therapy.Nature reviews. Cancer · 2018Review
- Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase.Journal of lipid research · 2017Article
- Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation.Scientific reports · 2017Article
- Alkaline ceramidase 2 and its bioactive product sphingosine are novel regulators of the DNA damage response.Oncotarget · 2016Article
- Activity of neutral and alkaline ceramidases on fluorogenic N-acylated coumarin-containing aminodiols.Journal of lipid research · 2015Article
- The Arabidopsis alkaline ceramidase TOD1 is a key turgor pressure regulator in plant cells.Nature communications · 2015Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Increased generation of dihydrosphingosine (DHS), a bioactive sphingolipid, has been implicated in the cytotoxicity of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) in tumor cells. However, how 4-HPR increases DHS remains unclear. Here we demonstrate that 4-HPR increases the expression of ACER2, which catalyzes the hydrolysis of dihydroceramides to generate DHS, and that ACER2 up-regulation plays a key role in mediating the 4-HPR-induced generation of DHS as well as the cytotoxicity of 4-HPR in tumor cells. Treatment with 4-HPR induced the accumulation of dihydroceramides (DHCs) in tumor cells by inhibiting dihydroceramide desaturase (DES) activity, which catalyzes the conversion of DHCs to ceramides. Treatment with 4-HPR also increased ACER2 expression through a retinoic acid receptor-independent and caspase-dependent manner. Overexpression of ACER2 augmented the 4-HPR-induced generation of DHS as well as 4-HPR cytotoxicity, and 4-HPR-induced death in tumor cells, whereas knocking down ACER2 had the opposite effects. ACER2 overexpression, along with treatment with GT11, another DES inhibitor, markedly increased cellular DHS, leading to tumor cell death, whereas ACER2 overexpression or GT11 treatment alone failed to do so, suggesting that both ACER2 up-regulation and DES inhibition are necessary and sufficient to mediate 4-HPR-induced DHS accumulation, cytotoxicity, and death in tumor cells. Taken together, these results suggest that up-regulation of the ACER2/DHS pathway mediates the cytotoxicity of 4-HPR in tumor cells and that up-regulating or activating ACER2 may improve the anti-cancer activity of 4-HRR and other DHC-inducing agents.
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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.