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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actin Cytoskeleton / drug effects
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Actin Cytoskeleton / metabolism*
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Actins / metabolism
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Androgen Receptor Antagonists / pharmacology*
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Androgen Receptor Antagonists / therapeutic use
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Biological Transport / drug effects
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Cell Communication / drug effects*
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Cell Culture Techniques
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Cell Line, Tumor
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Cell Survival / drug effects
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Chromones / pharmacology
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Clusterin / metabolism
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Coculture Techniques
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Drug Resistance, Neoplasm / drug effects*
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Epithelial Cells
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Humans
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Intravital Microscopy
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Male
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors / pharmacology
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Prostate / cytology
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Prostate / pathology
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Stress, Physiological / drug effects
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Wortmannin / pharmacology
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Y-Box-Binding Protein 1 / metabolism
Substances
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AR protein, human
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Actins
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Androgen Receptor Antagonists
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CLU protein, human
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Chromones
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Clusterin
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Androgen
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Y-Box-Binding Protein 1
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YBX1 protein, human
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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Wortmannin