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.
Highlights
In advanced prostate cancer (PCa), androgen receptor (AR) pathway inhibition (ARPI) induces profound and sustained responses
As progressing cancer cells encounter stress from metabolic demands and tissue hypoxia[36,37], we evaluated whether varied cellular stresses affect tunneling nanotubes (TNTs) formation
This work provides the first characterization of TNT formation in PCa as a means for stress adaptation and survival in the context of ARPI
Summary
In advanced prostate cancer (PCa), androgen receptor (AR) pathway inhibition (ARPI) induces profound and sustained responses. Progression to castration-resistant prostate cancer (CRPC) is inevitable and attributable to genomic and metabolic re-activation of the AR1 supported by context-dependent activation of stress response[2,3,4], kinase and developmental pathways[5,6] In addition to those induced by therapy, tumors are exposed to diverse stresses that are potentially lethal unless cells can acutely adapt to them. We previously defined several stress adaptive mechanisms that promote treatment resistance in cancer, including roles for stress adaptor proteins like YB-18, clusterin (CLU)[3] and Hsp[274] in pro-survival pathways activation[9,10,11]. We characterize the formation and features of TNTs in PCa cells after metabolic and ARPI stress and explore their roles in transport of stress-associated proteins involved in treatment resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
