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Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo

ABSTRACT: Pancreas ductal adenocarcinoma (PDAC) remains a malignant tumor with very poor prognosis and low 5-year overall survival. Here, we aimed to simultaneously target mitochondria and lysosomes as a new treatment paradigm of malignant pancreas cancer in vitro and in vivo. We demonstrate that th...

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Autores principales: Patel, Sameer H., Bachmann, Magdalena, Kadow, Stephanie, Wilson, Gregory C., Abdel-Salam, Mostafa M. L., Xu, Kui, Keitsch, Simone, Soddemann, Matthias, Wilker, Barbara, Becker, Katrin Anne, Carpinteiro, Alexander, Ahmad, Syed A., Szabo, Ildiko, Gulbins, Erich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10036429/
https://www.ncbi.nlm.nih.gov/pubmed/36790532
http://dx.doi.org/10.1007/s00109-023-02290-y
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author Patel, Sameer H.
Bachmann, Magdalena
Kadow, Stephanie
Wilson, Gregory C.
Abdel-Salam, Mostafa M. L.
Xu, Kui
Keitsch, Simone
Soddemann, Matthias
Wilker, Barbara
Becker, Katrin Anne
Carpinteiro, Alexander
Ahmad, Syed A.
Szabo, Ildiko
Gulbins, Erich
author_facet Patel, Sameer H.
Bachmann, Magdalena
Kadow, Stephanie
Wilson, Gregory C.
Abdel-Salam, Mostafa M. L.
Xu, Kui
Keitsch, Simone
Soddemann, Matthias
Wilker, Barbara
Becker, Katrin Anne
Carpinteiro, Alexander
Ahmad, Syed A.
Szabo, Ildiko
Gulbins, Erich
author_sort Patel, Sameer H.
collection PubMed
description ABSTRACT: Pancreas ductal adenocarcinoma (PDAC) remains a malignant tumor with very poor prognosis and low 5-year overall survival. Here, we aimed to simultaneously target mitochondria and lysosomes as a new treatment paradigm of malignant pancreas cancer in vitro and in vivo. We demonstrate that the clinically used sphingosine analog FTY-720 together with PAPTP, an inhibitor of mitochondrial Kv1.3, induce death of pancreas cancer cells in vitro and in vivo. The combination of both drugs results in a marked inhibition of the acid sphingomyelinase and accumulation of cellular sphingomyelin in vitro and in vivo in orthotopic and flank pancreas cancers. Mechanistically, PAPTP and FTY-720 cause a disruption of both mitochondria and lysosomes, an alteration of mitochondrial bioenergetics and accumulation of cytoplasmic Ca(2+), events that collectively mediate cell death. Our findings point to an unexpected cross-talk between lysosomes and mitochondria mediated by sphingolipid metabolism. We show that the combination of PAPTP and FTY-720 induces massive death of pancreas cancer cells, thereby leading to a substantially delayed and reduced PDAC growth in vivo. KEY MESSAGES: FTY-720 inhibits acid sphingomyelinase in pancreas cancer cells (PDAC). FTY-720 induces sphingomyelin accumulation and lysosomal dysfunction. The mitochondrial Kv1.3 inhibitor PAPTP disrupts mitochondrial functions. PAPTP and FTY-720 synergistically kill PDAC in vitro. The combination of FTY-720 and PAPTP greatly delays PDAC growth in vivo.
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spelling pubmed-100364292023-03-25 Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo Patel, Sameer H. Bachmann, Magdalena Kadow, Stephanie Wilson, Gregory C. Abdel-Salam, Mostafa M. L. Xu, Kui Keitsch, Simone Soddemann, Matthias Wilker, Barbara Becker, Katrin Anne Carpinteiro, Alexander Ahmad, Syed A. Szabo, Ildiko Gulbins, Erich J Mol Med (Berl) Original Article ABSTRACT: Pancreas ductal adenocarcinoma (PDAC) remains a malignant tumor with very poor prognosis and low 5-year overall survival. Here, we aimed to simultaneously target mitochondria and lysosomes as a new treatment paradigm of malignant pancreas cancer in vitro and in vivo. We demonstrate that the clinically used sphingosine analog FTY-720 together with PAPTP, an inhibitor of mitochondrial Kv1.3, induce death of pancreas cancer cells in vitro and in vivo. The combination of both drugs results in a marked inhibition of the acid sphingomyelinase and accumulation of cellular sphingomyelin in vitro and in vivo in orthotopic and flank pancreas cancers. Mechanistically, PAPTP and FTY-720 cause a disruption of both mitochondria and lysosomes, an alteration of mitochondrial bioenergetics and accumulation of cytoplasmic Ca(2+), events that collectively mediate cell death. Our findings point to an unexpected cross-talk between lysosomes and mitochondria mediated by sphingolipid metabolism. We show that the combination of PAPTP and FTY-720 induces massive death of pancreas cancer cells, thereby leading to a substantially delayed and reduced PDAC growth in vivo. KEY MESSAGES: FTY-720 inhibits acid sphingomyelinase in pancreas cancer cells (PDAC). FTY-720 induces sphingomyelin accumulation and lysosomal dysfunction. The mitochondrial Kv1.3 inhibitor PAPTP disrupts mitochondrial functions. PAPTP and FTY-720 synergistically kill PDAC in vitro. The combination of FTY-720 and PAPTP greatly delays PDAC growth in vivo. Springer Berlin Heidelberg 2023-02-15 2023 /pmc/articles/PMC10036429/ /pubmed/36790532 http://dx.doi.org/10.1007/s00109-023-02290-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Patel, Sameer H.
Bachmann, Magdalena
Kadow, Stephanie
Wilson, Gregory C.
Abdel-Salam, Mostafa M. L.
Xu, Kui
Keitsch, Simone
Soddemann, Matthias
Wilker, Barbara
Becker, Katrin Anne
Carpinteiro, Alexander
Ahmad, Syed A.
Szabo, Ildiko
Gulbins, Erich
Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo
title Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo
title_full Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo
title_fullStr Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo
title_full_unstemmed Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo
title_short Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo
title_sort simultaneous targeting of mitochondrial kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10036429/
https://www.ncbi.nlm.nih.gov/pubmed/36790532
http://dx.doi.org/10.1007/s00109-023-02290-y
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