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Cited by 24Sphingolipid Metabolism and SignalingRetinoids in leukemia and cellular processesHedgehog Signaling Pathway Studies

Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination

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Shi, Wen-Na, Cui, Shu-Xiang, Song, Zhi-Yu, Wang, Shu-Qing, Sun, Shi-Yue, Yu, Xin-Feng, Li, Ye, Zhang, Yu-Hang +2 more·2017·Oncotarget
DOI 10.18632/oncotarget.17174PMC PMC5503636
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Abstract

// Wen-Na Shi 1 , Shu-Xiang Cui 2 , Zhi-Yu Song 1 , Shu-Qing Wang 1 , Shi-Yue Sun 1 , Xin-Feng Yu 1 , Ye Li 1 , Yu-Hang Zhang 1 , Zu-Hua Gao 3 and Xian-Jun Qu 1 1 Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China 2 Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China 3 Department of Pathology, McGill University, Montreal, Quebec, Canada Correspondence to: Xian-Jun Qu, email: quxj@ccmu.edu.cn Zu-Hua Gao, email: zu-hua.gao@mcgill.ca Keywords: sphingosine kinase 2 (SphK2), retinoid therapy resistance, cytoplasmic RXRα, polyubiquitination Received: December 06, 2016 Accepted: March 26, 2017 Published: April 18, 2017 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-116 Sphk2 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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  • RXRα expression is decreased in U87-SphK2 cells.

    “RXRα expression is decreased in U87-SphK2 cells (supplemental Fig. S8)”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [39]

    The Results section reports decreased RXRα expression in HCT-116Sphk2 cells after ATRA treatment. The cited paper studies HCT-116 cells, not U87-SphK2 cells, so it does not establish the claimed result in that cell line. (LLM, conf=0.87)

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  • SphK2 overexpression resulted in the downregulation of endogenous RXRα, but not of LXRα/β.

    “Interestingly, as previously reported in all-trans retinoic acid-resistant colon cancer cells, SphK2 overexpression resulted in the downregulation of endogenous RXRα (39), but not of LXRα/β (supplemental Fig. S8A–C).”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [39]

  • SphK2 overexpression downregulates endogenous RXRα in all-trans retinoic acid-resistant colon cancer cells.

    “Interestingly, as previously reported in all-trans retinoic acid-resistant colon cancer cells, SphK2 overexpression resulted in the downregulation of endogenous RXRα (39), but not of LXRα/β (supplemental Fig. S8A–C).”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [39]

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Authors
Shi, W.-N., Cui, S.-X., Song, Z.-Y., Wang, S.-Q., Sun, S.-Y., Yu, X.-F., Li, Y., Zhang, Y.-H., Gao, Z.-H., & Qu, X.-J.
Affiliations
  • Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
  • Capital Medical University (CN)
Corresponding author
Gao, Zu-Hua
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2017-04-18
Volume
8
Issue
24
Pages
39605-39617
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.17174
PMC
PMC5503636
OpenAlex
W2607307743
Cited by
24
References
3
Citations by year
2025: 2 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 3
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • McGill University
  • McGill University Health Centre
  • National Natural Science Foundation of China (81373435, 81373436, 91229113)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
Keywords
sphingosine kinase 2, all-trans retinoic acid resistance, colon cancer, retinoid X receptor alpha, K48-linked polyubiquitination, K63-linked ubiquitination, ubiquitination, nuclear export, HCT116 cells
MeSH terms
Sphingosine Kinase, Animals, Autophagy, Colonic Neoplasms, Disease Models, Animal, Humans, Ligands, Protein Binding, Tretinoin, Ubiquitins, Gene Expression, Phosphotransferases (Alcohol Group Acceptor), Drug Resistance, Neoplasm, Protein Transport, Xenograft Model Antitumor Assays, HCT116 Cells, Tumor Burden, Retinoid X Receptor alpha, Mice, Ubiquitination, Proteolysis

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