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Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer.
- Source :
-
Scientific reports [Sci Rep] 2019 May 24; Vol. 9 (1), pp. 7826. Date of Electronic Publication: 2019 May 24. - Publication Year :
- 2019
-
Abstract
- Tunneling nanotubes (TNTs) are actin-based membranous structures bridging distant cells for intercellular communication. We define roles for TNTs in stress adaptation and treatment resistance in prostate cancer (PCa). Androgen receptor (AR) blockade and metabolic stress induce TNTs, but not in normal prostatic epithelial or osteoblast cells. Co-culture assays reveal enhanced TNT formation between stressed and unstressed PCa cells as well as from stressed PCa to osteoblasts. Stress-induced chaperones clusterin and YB-1 localize within TNTs, are transported bi-directionally via TNTs and facilitate TNT formation in PI3K/AKT and Eps8-dependent manner. AR variants, induced by AR antagonism to mediate resistance to AR pathway inhibition, also enhance TNT production and rescue loss of clusterin- or YB-1-repressed TNT formation. TNT disruption sensitizes PCa to treatment-induced cell death. These data define a mechanistic network involving stress induction of chaperone and AR variants, PI3K/AKT signaling, actin remodeling and TNT-mediated intercellular communication that confer stress adaptative cell survival.
- Subjects :
- Actin Cytoskeleton drug effects
Actins metabolism
Androgen Receptor Antagonists therapeutic use
Biological Transport drug effects
Cell Culture Techniques
Cell Line, Tumor
Cell Survival drug effects
Chromones pharmacology
Clusterin metabolism
Coculture Techniques
Epithelial Cells
Humans
Intravital Microscopy
Male
Morpholines pharmacology
Phosphatidylinositol 3-Kinases metabolism
Phosphoinositide-3 Kinase Inhibitors pharmacology
Prostate cytology
Prostate pathology
Prostatic Neoplasms pathology
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Proto-Oncogene Proteins c-akt metabolism
Receptors, Androgen genetics
Receptors, Androgen metabolism
Signal Transduction drug effects
Signal Transduction genetics
Stress, Physiological drug effects
Wortmannin pharmacology
Y-Box-Binding Protein 1 metabolism
Actin Cytoskeleton metabolism
Androgen Receptor Antagonists pharmacology
Cell Communication drug effects
Drug Resistance, Neoplasm drug effects
Prostatic Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 31127190
- Full Text :
- https://doi.org/10.1038/s41598-019-44346-5