Tumor hypoxia regulates ganglioside GM3 synthase, which contributes to oxidative stress resistance in malignant melanoma
| Autor: | Nagako Kawashima, Tadashi Yamashita, Takuya Maruo, Yuki Nemoto, Takuto Shimizu, Mira Suzuki, Masaki Nagane, Yasushi Kawakami, Akinori Yamauchi, Kazuhiro Kato |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Programmed cell death Skin Neoplasms Biophysics Melanoma Experimental medicine.disease_cause Biochemistry 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor medicine Animals G(M3) Ganglioside Humans Molecular Biology Lipid raft Melanoma Tumor microenvironment Tumor hypoxia Chemistry Endoplasmic reticulum Hypoxia (medical) Sialyltransferases Cell biology Mice Inbred C57BL Oxidative Stress 030104 developmental biology 030220 oncology & carcinogenesis Tumor Hypoxia lipids (amino acids peptides and proteins) Female medicine.symptom Oxidative stress |
| Zdroj: | Biochimica et biophysica acta. General subjects. 1864(12) |
| ISSN: | 1872-8006 |
| Popis: | Background: Tumor hypoxia drastically changes cancer phenotypes, including angiogenesis, invasion, and cell death. Gangliosides are sialic acid-containing glycosphingolipids that are ubiquitously distributed on plasma membranes and are involved in many biological processes, such as the endoplasmic reticulum stress response and apoptosis. In this study, we investigated the regulation and function of glycosphingolipids, which associate with lipid raft on mammalian plasma membranes under hypoxic condition. Methods: B16F10 melanoma cells were subjected to chemical hypoxia and low pO2 condition, and the effect of hypoxia on expression of GM3 synthase were analyzed. Cellular resistance to oxidative stress was analyzed in GM3S-KO B16F10 cells. Results: Hypoxia treatment decreased the expression of ganglioside GM3 synthase (GM3S; ST3GAL5), which synthesizes the common substrate of ganglioside biosynthesis. RNA interference of hypoxia inducible factor 1 subunit alpha (HIF-1α) inhibited hypoxia-induced GM3S suppression. Additionally, GM3S deficiency increased cellular resistance to oxidative stress and radiation therapy via upregulation of ERK. Conclusions: Altered synthesis of glycosphingolipids downstream of HIF-1α signaling increased the resistance of melanoma cells to oxidative stress. Furthermore, GM3 has important role on cellular adaptive response to hypoxia. General significance: This study indicates that tumor hypoxia regulates therapy-resistance via modulation of ganglioside synthesis. |
| Databáze: | OpenAIRE |
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