Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth
Abstract Sphingosine kinase 1 (SphK1) and sphingosine kinase (SphK2) are both important therapeutic targets of non-small cell lung cancer (NSCLC). SKI-349 is a novel, highly efficient and small molecular SphK1/2 dual inhibitor. Here in primary human NSCLC cells and immortalized cell lines, SKI-349 p...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-07-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05049-4 |
| _version_ | 1818474216633139200 |
|---|---|
| author | Yuhang Xue Kanqiu Jiang Li Ou Mingjing Shen Yi Yang Jingjing Lu Weihua Xu |
| author_facet | Yuhang Xue Kanqiu Jiang Li Ou Mingjing Shen Yi Yang Jingjing Lu Weihua Xu |
| author_sort | Yuhang Xue |
| collection | DOAJ |
| description | Abstract Sphingosine kinase 1 (SphK1) and sphingosine kinase (SphK2) are both important therapeutic targets of non-small cell lung cancer (NSCLC). SKI-349 is a novel, highly efficient and small molecular SphK1/2 dual inhibitor. Here in primary human NSCLC cells and immortalized cell lines, SKI-349 potently inhibited cell proliferation, cell cycle progression, migration and viability. The dual inhibitor induced mitochondrial depolarization and apoptosis activation in NSCLC cells, but it was non-cytotoxic to human lung epithelial cells. SKI-349 inhibited SphK activity and induced ceramide accumulation in primary NSCLC cells, without affecting SphK1/2 expression. SKI-349-induced NSCLC cell death was attenuated by sphingosine-1-phosphate and by the SphK activator K6PC-5, but was potentiated by the short-chain ceramide C6. Moreover, SKI-349 induced Akt-mTOR inactivation, JNK activation, and oxidative injury in primary NSCLC cells. In addition, SKI-349 decreased bromodomain-containing protein 4 (BRD4) expression and downregulated BRD4-dependent genes (Myc, cyclin D1 and Klf4) in primary NSCLC cells. At last, SKI-349 (10 mg/kg) administration inhibited NSCLC xenograft growth in nude mice. Akt-mTOR inhibition, JNK activation, oxidative injury and BRD4 downregulation were detected in SKI-349-treated NSCLC xenograft tissues. Taken together, targeting SphK1/2 by SKI-349 potently inhibits NSCLC cell growth in vitro and in vivo. |
| first_indexed | 2024-04-14T04:35:01Z |
| format | Article |
| id | doaj.art-739f3e91e8e546069af3a84394a04e69 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-14T04:35:01Z |
| publishDate | 2022-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-739f3e91e8e546069af3a84394a04e692022-12-22T02:11:55ZengNature Publishing GroupCell Death and Disease2041-48892022-07-0113711110.1038/s41419-022-05049-4Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growthYuhang Xue0Kanqiu Jiang1Li Ou2Mingjing Shen3Yi Yang4Jingjing Lu5Weihua Xu6Department of Thoracic Surgery, the Second Affiliated Hospital of Soochow UniversityDepartment of Thoracic Surgery, the Second Affiliated Hospital of Soochow UniversityDepartment of Gynecology and Obstetrics, The Second Affiliated Hospital Soochow UniversityDepartment of Thoracic Surgery, the Second Affiliated Hospital of Soochow UniversityDepartment of Nuclear Medicine, the Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical UniversityDepartment of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu UniversityDepartment of Thoracic Surgery, the Second Affiliated Hospital of Soochow UniversityAbstract Sphingosine kinase 1 (SphK1) and sphingosine kinase (SphK2) are both important therapeutic targets of non-small cell lung cancer (NSCLC). SKI-349 is a novel, highly efficient and small molecular SphK1/2 dual inhibitor. Here in primary human NSCLC cells and immortalized cell lines, SKI-349 potently inhibited cell proliferation, cell cycle progression, migration and viability. The dual inhibitor induced mitochondrial depolarization and apoptosis activation in NSCLC cells, but it was non-cytotoxic to human lung epithelial cells. SKI-349 inhibited SphK activity and induced ceramide accumulation in primary NSCLC cells, without affecting SphK1/2 expression. SKI-349-induced NSCLC cell death was attenuated by sphingosine-1-phosphate and by the SphK activator K6PC-5, but was potentiated by the short-chain ceramide C6. Moreover, SKI-349 induced Akt-mTOR inactivation, JNK activation, and oxidative injury in primary NSCLC cells. In addition, SKI-349 decreased bromodomain-containing protein 4 (BRD4) expression and downregulated BRD4-dependent genes (Myc, cyclin D1 and Klf4) in primary NSCLC cells. At last, SKI-349 (10 mg/kg) administration inhibited NSCLC xenograft growth in nude mice. Akt-mTOR inhibition, JNK activation, oxidative injury and BRD4 downregulation were detected in SKI-349-treated NSCLC xenograft tissues. Taken together, targeting SphK1/2 by SKI-349 potently inhibits NSCLC cell growth in vitro and in vivo.https://doi.org/10.1038/s41419-022-05049-4 |
| spellingShingle | Yuhang Xue Kanqiu Jiang Li Ou Mingjing Shen Yi Yang Jingjing Lu Weihua Xu Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth Cell Death and Disease |
| title | Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth |
| title_full | Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth |
| title_fullStr | Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth |
| title_full_unstemmed | Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth |
| title_short | Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth |
| title_sort | targeting sphingosine kinase 1 2 by a novel dual inhibitor ski 349 suppresses non small cell lung cancer cell growth |
| url | https://doi.org/10.1038/s41419-022-05049-4 |
| work_keys_str_mv | AT yuhangxue targetingsphingosinekinase12byanoveldualinhibitorski349suppressesnonsmallcelllungcancercellgrowth AT kanqiujiang targetingsphingosinekinase12byanoveldualinhibitorski349suppressesnonsmallcelllungcancercellgrowth AT liou targetingsphingosinekinase12byanoveldualinhibitorski349suppressesnonsmallcelllungcancercellgrowth AT mingjingshen targetingsphingosinekinase12byanoveldualinhibitorski349suppressesnonsmallcelllungcancercellgrowth AT yiyang targetingsphingosinekinase12byanoveldualinhibitorski349suppressesnonsmallcelllungcancercellgrowth AT jingjinglu targetingsphingosinekinase12byanoveldualinhibitorski349suppressesnonsmallcelllungcancercellgrowth AT weihuaxu targetingsphingosinekinase12byanoveldualinhibitorski349suppressesnonsmallcelllungcancercellgrowth |