ArticleOncotarget2017
Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination.
Article in Oncotarget, 2017. 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, 25 citations in OpenAlex.
- Article
- Targeting the retinoic acid signaling pathway as a modern precision therapy against cancers.Frontiers in cell and developmental biology · 2023Review
- Role of K63-linked ubiquitination in cancer.Cell death discovery · 2022Review
- Downregulation of Lipid Phosphate Phosphatase 3 Correlates With Tumor-Infiltrating Immune Cells in Oral Cancer.Cureus · 2022Article
- METTL3-mediated mOncogene · 2021Article
- Article
- Regulation of hypoxia-inducible factor functions in the nucleus by sphingosine-1-phosphate.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Retinoic Acids in the Treatment of Most Lethal Solid Cancers.Journal of clinical medicine · 2020Review
- Targeting SphK2 Reverses Acquired Resistance of Regorafenib in Hepatocellular Carcinoma.Frontiers in oncology · 2020Article
- Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer's disease brain.Acta neuropathologica communications · 2018Article
- SphK2 over-expression promotes osteosarcoma cell growth.Oncotarget · 2017Article
- Sphingosine Kinases and Sphingosine 1-Phosphate Receptors: Signaling and Actions in the Cardiovascular System.Frontiers in pharmacology · 2017Review
- The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer.Mediators of inflammation · 2017Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The resistance mechanisms that limit the efficacy of retinoid therapy in cancer are poorly understood. Sphingosine kinase 2 (SphK2) is a highly conserved enzyme that is mainly located in the nucleus and endoplasmic reticulum. Unlike well-studied sphingosine kinase 1 (SphK1) located in the cytosol, little has yet understood the functions of SphK2. Here we show that SphK2 overexpression contributes to the resistance of all-trans retinoic acid (ATRA) therapy in colon cancer through rapid degradation of cytoplasmic retinoid X receptor α (RXRα) by lysine 48 (K48)- and lysine 63 (K63)-based polyubiquitination. Human colonic adenocarcinoma HCT-116 cells transfected with SphK2 (HCT-116Sphk2 cells) demonstrate resistance to ATRA therapy as determined by in vitro and in vivo assays. Sphk2 overexpression increases the ATRA-induced nuclear RXRα export to cytoplasm and then rapidly degrades RXRα through the polyubiquitination pathway. We further show that Sphk2 activates the ubiquitin-proteasome system through the signal mechanisms of (1) K48-linked proteosomal degradation and (2) K63-linked ubiquitin-dependent autophagic degradation. These results provide new insights into the biological functions of Sphk2 and the molecular mechanisms that underlie the Sphk2-mediated resistance to retinoid therapy.
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