Sphingosine is involved in PAPTP-induced death of pancreas cancer cells by interfering with mitochondrial functions
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| Názov: | Sphingosine is involved in PAPTP-induced death of pancreas cancer cells by interfering with mitochondrial functions |
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| Autori: | Patel, Sameer H., Wilson, Gregory C., Wu, Yuqing, Keitsch, Simone, Wilker, Barbara, Mattarei, Andrea, Ahmad, Syed A., Szabo, Ildiko, Gulbins, Erich |
| Zdroj: | J Mol Med (Berl) |
| Informácie o vydavateľovi: | Springer Science and Business Media LLC, 2024. |
| Rok vydania: | 2024 |
| Predmety: | 0301 basic medicine, 0303 health sciences, Kv1.3 Potassium Channel, Cell Death, Medizin, Mitochondria, Cell Line, Tumor [MeSH], Proto-Oncogene Proteins p21(ras)/metabolism [MeSH], Pancreatic Neoplasms/pathology [MeSH], Proto-Oncogene Proteins p21(ras)/genetics [MeSH], Original Article, Cell Death/drug effects [MeSH], Kv1.3, Kv1.3 Potassium Channel/antagonists, Carcinoma, Pancreatic Ductal/metabolism [MeSH], Pancreatic Neoplasms/genetics [MeSH], Mitochondria/metabolism [MeSH], Humans [MeSH], Kv1.3 Potassium Channel/genetics [MeSH], Kv1.3 Potassium Channel/metabolism [MeSH], Animals [MeSH], Pancreatic Neoplasms/drug therapy [MeSH], Cytochrome C, Carcinoma, Pancreatic Ductal/genetics [MeSH], Sphingosine/analogs, Carcinoma, Pancreatic Ductal/drug therapy [MeSH], Mice [MeSH], Pancreas cancer, Sphingosine/metabolism [MeSH], Carcinoma, Pancreatic Ductal/pathology [MeSH], Mitochondria/drug effects [MeSH], Pancreatic Neoplasms/metabolism [MeSH], Sphingosine, 3. Good health, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Mice, 03 medical and health sciences, Cell Line, Tumor, Humans, Animals, Carcinoma, Pancreatic Ductal |
| Popis: | Abstract Pancreas ductal adenocarcinoma belongs to the most common cancers, but also to the tumors with the poorest prognosis. Here, we pharmacologically targeted a mitochondrial potassium channel, namely mitochondrial Kv1.3, and investigated the role of sphingolipids and mutated Kirsten Rat Sarcoma Virus (KRAS) in Kv1.3-mediated cell death. We demonstrate that inhibition of Kv1.3 using the Kv1.3-inhibitor PAPTP results in an increase of sphingosine and superoxide in membranes and/or membranes associated with mitochondria, which is enhanced by KRAS mutation. The effect of PAPTP on sphingosine and mitochondrial superoxide formation as well as cell death is prevented by sh-RNA-mediated downregulation of Kv1.3. Induction of sphingosine in human pancreas cancer cells by PAPTP is mediated by activation of sphingosine-1-phosphate phosphatase and prevented by an inhibitor of sphingosine-1-phosphate phosphatase. A rapid depolarization of isolated mitochondria is triggered by binding of sphingosine to cardiolipin, which is neutralized by addition of exogenous cardiolipin. The significance of these findings is indicated by treatment of mutated KRAS-harboring metastasized pancreas cancer with PAPTP in combination with ABC294640, a blocker of sphingosine kinases. This treatment results in increased formation of sphingosine and death of pancreas cancer cells in vitro and, most importantly, prolongs in vivo survival of mice challenged with metastatic pancreas cancer. Key messages Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. The mitochondrial Kv1.3 ion channel blocker induced mitochondrial sphingosine. Sphingosine binds to cardiolipin thereby mediating mitochondrial depolarization. Sphingosine is formed by a PAPTP-mediated activation of S1P-Phosphatase. Inhibition of sphingosine-consumption amplifies PAPTP effects on PDAC in vivo. |
| Druh dokumentu: | Article Other literature type |
| Popis súboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1432-1440 0946-2716 |
| DOI: | 10.1007/s00109-024-02456-2 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/38780771 https://hdl.handle.net/11577/3515924 https://doi.org/10.1007/s00109-024-02456-2 https://repository.publisso.de/resource/frl:6518160 https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&origin=inward&scp=85193940138 https://www.ncbi.nlm.nih.gov/pubmed/38780771 https://doi.org/10.1007/s00109-024-02456-2 |
| Rights: | CC BY |
| Prístupové číslo: | edsair.doi.dedup.....4f80d7476f555b8d22f1b3ac42e9c58b |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Abstract Pancreas ductal adenocarcinoma belongs to the most common cancers, but also to the tumors with the poorest prognosis. Here, we pharmacologically targeted a mitochondrial potassium channel, namely mitochondrial Kv1.3, and investigated the role of sphingolipids and mutated Kirsten Rat Sarcoma Virus (KRAS) in Kv1.3-mediated cell death. We demonstrate that inhibition of Kv1.3 using the Kv1.3-inhibitor PAPTP results in an increase of sphingosine and superoxide in membranes and/or membranes associated with mitochondria, which is enhanced by KRAS mutation. The effect of PAPTP on sphingosine and mitochondrial superoxide formation as well as cell death is prevented by sh-RNA-mediated downregulation of Kv1.3. Induction of sphingosine in human pancreas cancer cells by PAPTP is mediated by activation of sphingosine-1-phosphate phosphatase and prevented by an inhibitor of sphingosine-1-phosphate phosphatase. A rapid depolarization of isolated mitochondria is triggered by binding of sphingosine to cardiolipin, which is neutralized by addition of exogenous cardiolipin. The significance of these findings is indicated by treatment of mutated KRAS-harboring metastasized pancreas cancer with PAPTP in combination with ABC294640, a blocker of sphingosine kinases. This treatment results in increased formation of sphingosine and death of pancreas cancer cells in vitro and, most importantly, prolongs in vivo survival of mice challenged with metastatic pancreas cancer. Key messages Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. The mitochondrial Kv1.3 ion channel blocker induced mitochondrial sphingosine. Sphingosine binds to cardiolipin thereby mediating mitochondrial depolarization. Sphingosine is formed by a PAPTP-mediated activation of S1P-Phosphatase. Inhibition of sphingosine-consumption amplifies PAPTP effects on PDAC in vivo. |
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| ISSN: | 14321440 09462716 |
| DOI: | 10.1007/s00109-024-02456-2 |