1. Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer.
- Author
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Kretschmer A, Zhang F, Somasekharan SP, Tse C, Leachman L, Gleave A, Li B, Asmaro I, Huang T, Kotula L, Sorensen PH, and Gleave ME
- 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
- 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.
- Published
- 2019
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