Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth
Abstract Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06023-4 |
| _version_ | 1797736381474144256 |
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| author | Lu Jin Jin Zhu Linya Yao Gang Shen Bo-xin Xue Wei Tao |
| author_facet | Lu Jin Jin Zhu Linya Yao Gang Shen Bo-xin Xue Wei Tao |
| author_sort | Lu Jin |
| collection | DOAJ |
| description | Abstract Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo. |
| first_indexed | 2024-03-12T13:11:56Z |
| format | Article |
| id | doaj.art-0264267386d54da287dc1a0485851f3d |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T13:11:56Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-0264267386d54da287dc1a0485851f3d2023-08-27T11:30:07ZengNature Publishing GroupCell Death and Disease2041-48892023-08-0114811410.1038/s41419-023-06023-4Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growthLu Jin0Jin Zhu1Linya Yao2Gang Shen3Bo-xin Xue4Wei Tao5Department of Urology, the Second Affiliated Hospital of Soochow UniversityDepartment of Urology, the Second Affiliated Hospital of Soochow UniversityDepartment of Urology, Kunshan Hospital of Traditional Chinese Medicine Affiliated to Yangzhou UniversityDepartment of Urology, DUSHU Lake Hospital Affiliated to Soochow UniversityDepartment of Urology, the Second Affiliated Hospital of Soochow UniversityDepartment of Urology, the Second Affiliated Hospital of Soochow UniversityAbstract Sphingosine kinases (SphK), including SphK1 and SphK2, are important enzymes promoting progression of prostate cancer. SKI-178 is a novel and highly potent SphK1/2 dual inhibitor. We here tested the potential anti-prostate cancer cell activity of SKI-178. Bioinformatics analyses and results from local tissues demonstrated that that both SphK1 and SphK2 are upregulated in human prostate cancer tissues. Ectopic overexpression of SphK1 and SphK2, by lentiviral constructs, promoted primary prostate cancer cell proliferation and migration. In primary human prostate cancer cells and immortalized cell lines, SKI-178 potently inhibited cell viability, proliferation, cell cycle progression and cell migration, causing robust cell death and apoptosis. SKI-178 impaired mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production and ATP depletion.SKI-178 potently inhibited SphK activity and induced ceramide production, without affecting SphK1/2 expression in prostate cancer cells. Further, SKI-178 inhibited Akt-mTOR activation and induced JNK activation in prostate cancer cells. Contrarily, a constitutively-active Akt1 construct or the pharmacological JNK inhibitors attenuated SKI-178-induced cytotoxicity in prostate cancer cells. In vivo, daily intraperitoneal injection of a single dose of SKI-178 potently inhibited PC-3 xenograft growth in nude mice. SphK inhibition, ceramide production, ATP depletion and lipid peroxidation as well as Akt-mTOR inactivation and JNK activation were detected in PC-3 xenograft tissues with SKI-178 administration. Together, targeting SphK1/2 by SKI-178 potently inhibited prostate cancer cell growth in vitro and in vivo.https://doi.org/10.1038/s41419-023-06023-4 |
| spellingShingle | Lu Jin Jin Zhu Linya Yao Gang Shen Bo-xin Xue Wei Tao Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth Cell Death and Disease |
| title | Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth |
| title_full | Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth |
| title_fullStr | Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth |
| title_full_unstemmed | Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth |
| title_short | Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth |
| title_sort | targeting sphk1 2 by ski 178 inhibits prostate cancer cell growth |
| url | https://doi.org/10.1038/s41419-023-06023-4 |
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