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
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