ArticleFEBS open bio2018
A role for caspase-2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells - implications for the CHK1-suppressed pathway.
Article in FEBS open bio, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 22 citations in OpenAlex.
- An integrative approach to studying sphingolipid metabolism reveals p53 as a master regulator of the pathway.Journal of lipid research · 2026Article
- Limited Proteolysis as a Regulator of Lymphatic Vessel Function and Architecture.International journal of molecular sciences · 2025Review
- Molecular dynamics investigation on synthesis of a pH- and temperature-sensitive carbon nanotube loaded with doxorubicin.iScience · 2024Article
- Targeting sphingosine kinase 1 in p53KO thymic lymphoma.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2023Article
- Upregulation of sphingosine kinase 1 in response to doxorubicin generates an angiogenic response via stabilization of Snail.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2023Article
- Cytotoxic mechanisms of doxorubicin at clinically relevant concentrations in breast cancer cells.Cancer chemotherapy and pharmacology · 2022Review
- Bioactive sphingolipids: Advancements and contributions from the laboratory of Dr. Lina M. Obeid.Cellular signalling · 2021Review
- Sphingosine kinase 1 downregulation is required for adaptation to serine deprivation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Dysregulation of lysophospholipid signaling by p53 in malignant cells and the tumor microenvironment.Cellular signalling · 2021Review
- Molecular engineering of the last-generation CNTs in smart cancer therapy by grafting PEG-PLGA-riboflavin.RSC advances · 2020Article
- Nuclear Lipid Microdomains Regulate Daunorubicin Resistance in Hepatoma Cells.International journal of molecular sciences · 2018Article
- Ceramide Signaling and p53 Pathways.Advances in cancer research · 2018Review
- The Tumorigenic Effect of Sphingosine Kinase 1 and Its Potential Therapeutic Target.Cancer control : journal of the Moffitt Cancer CenterReview
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1-phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have demonstrated that SK1 proteolysis occurs downstream of the tumor suppressor p53 in response to several DNA-damaging agents. Moreover, loss of SK1 in p53-knockout mice resulted in complete protection from thymic lymphoma, providing evidence that regulation of SK1 constitutes a major tumor suppressor function of p53. Given this profound phenotype, this study aimed to investigate the mechanism by which wild-type p53 regulates proteolysis of SK1 in response to the DNA-damaging agent doxorubicin in breast cancer cells. We find that p53-mediated activation of caspase-2 was required for SK1 proteolysis and that caspase-2 activity significantly alters the levels of endogenous sphingolipids. As p53 is mutated in 50% of all cancers, we extended our studies to investigate whether SK1 is deregulated in the context of triple-negative breast cancer cells (TNBC) harboring a mutation in p53. Indeed, caspase-2 was not activated in these cells and SK1 was not degraded. Moreover, caspase-2 activation was recently shown to be downstream of the CHK1-suppressed pathway in p53-mutant cells, whereby inhibition of the cell cycle kinase CHK1 leads to caspase-2 activation and apoptosis. Indeed, knockdown and inhibition of CHK1 led to the loss of SK1 in p53-mutant TNBC cells, providing evidence that SK1 may be the first identified effector of the CHK1-suppressed pathway.
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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.