Caveolin-1 regulates the ASMase/ceramide-mediated radiation response of endothelial cells in the context of tumor–stroma interactions
Autor: | Julia Ketteler, Daniela Leonetti, Hala Estephan, Verena Jendrossek, Diana Klein, Patrick Maier, Alina Wittka, Victoria Veas Roy, Henning Reis, Carsten Herskind, François Paris |
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Přispěvatelé: | Bernardo, Elizabeth, University of Duisburg-Essen, Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universität Mannheim [Mannheim], Medizinische Fakultät Mannheim, This work was supported by grants of the DFG (GRK1739/1, GRK1739/2) and the BMBF (02NUK047D)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA) |
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer microenvironment Male Cancer Research Ceramide MAP Kinase Signaling System Immunology Caveolin 1 Medizin [SDV.CAN]Life Sciences [q-bio]/Cancer Apoptosis Cell Communication Ceramides Radiation Tolerance Article 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine [SDV.CAN] Life Sciences [q-bio]/Cancer Hsp27 Cell Line Tumor LNCaP medicine Tumor Microenvironment Humans lcsh:QH573-671 Protein kinase A Protein kinase B biology Chemistry lcsh:Cytology Endothelial Cells Prostatic Neoplasms Cell Biology Translational research Cancer therapeutic resistance 030104 developmental biology Sphingomyelin Phosphodiesterase 030220 oncology & carcinogenesis Cancer cell PC-3 Cells Cancer research biology.protein Acid sphingomyelinase Stromal Cells medicine.drug Signal Transduction |
Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 4, Pp 1-15 (2020) Cell Death and Disease Cell Death and Disease, 2020, 11 (4), pp.228. ⟨10.1038/s41419-020-2418-z⟩ Cell Death and Disease, Nature Publishing Group, 2020, 11 (4), pp.228. ⟨10.1038/s41419-020-2418-z⟩ |
ISSN: | 2041-4889 |
DOI: | 10.1038/s41419-020-2418-z⟩ |
Popis: | The integral membrane protein caveolin-1 (CAV1) plays a central role in radioresistance-mediating tumor–stroma interactions of advanced prostate cancer (PCa). Among the tumor–stroma, endothelial cells (EC) evolved as critical determinants of the radiation response. CAV1 deficiency in angiogenic EC was already shown to account for increased apoptosis rates of irradiated EC. This study explores the potential impact of differential CAV1 levels in EC on the acid sphingomyelinase (ASMase)/ceramide pathway as a key player in the regulation of EC apoptosis upon irradiation and cancer cell radioresistance. Enhanced apoptosis sensitivity of CAV1-deficient EC was associated with increased ASMase activity, ceramide generation, formation of large lipid platforms, and finally an altered p38 mitogen-activated protein kinase (MAPK)/heat-shock protein 27 (HSP27)/AKT (protein kinase B, PKB) signaling. CAV1-deficient EC increased the growth delay of LNCaP and PC3 PCa cells upon radiation treatment in direct 3D spheroid co-cultures. Exogenous C6 and C16 ceramide treatment in parallel increased the growth delay of PCa spheroids and induced PCa cell apoptosis. Analysis of the respective ceramide species in PCa cells with increased CAV1 levels like those typically found in radio-resistant advanced prostate tumors further revealed an upregulation of unsaturated C24:1 ceramide that might scavenge the effects of EC-derived apoptosis-inducing C16 ceramide. Higher ASMase as well as ceramide levels could be confirmed by immunohistochemistry in human advanced prostate cancer specimen bearing characteristic CAV1 tumor–stroma alterations. Conclusively, CAV1 critically regulates the generation of ceramide-dependent (re-)organization of the plasma membrane that in turn affects the radiation response of EC and adjacent PCa cells. Understanding the CAV1-dependent crosstalk between tumor cells and the host-derived tumor microvasculature and its impact on radiosensitivity may allow to define a rational strategy for overcoming tumor radiation resistance improving clinical outcomes by targeting CAV1. |
Databáze: | OpenAIRE |
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