Abstract
Cellular senescence is considered as a tumor suppressive mechanism. Recent evidence indicates however that senescent cells secrete various growth factors and cytokines, some of which may paradoxically promote cancer progression. This phenomenon termed senescence-associated secretory phenotype (SASP) must be inhibited in order for anti-proliferative agents to be effective. The present study was designed to determine whether the β-catenin destruction complex (BCDC), known to integrate the action of various growth factors and cytokines, would represent a suitable target to inhibit the activity of SASP components. For this, we carried out experiments to determine the effect of drug-induced senescence on secretion of SASP, β-catenin transactivation, and the relationship between these processes. Moreover, genetic and pharmacological approaches were used to define the implication of BCDC in mediating the effects of SASP components on cell migration and resistance to drugs. The findings indicate that drug-induced senescence was associated with expression of various Wnt ligands in addition to previously known SASP components. Beta catenin transactivation and expression of genes implicated in epithelial-mesenchymal transition (EMT) also increased in response to drug-induced SASP. These effects were prevented by Pyrvinium, a recently described activator of BCDC. Pyrvinium also suppressed the effects of SASP on cell migration and resistance to doxorubicin. Together, these findings provide insights on the potential role of BCDC in mediating the effects of drug-induced SASP on cancer cell invasion and resistance to therapy, and suggest that targeting this pathway may represent an effective approach to enhance the activity of current and prospective anti-cancer therapeutics.
Highlights
Cellular senescence is a signal transduction program that leads to irreversible proliferation arrest in response to endogenous or exogenous stressors [1]
We reasoned that such target could be the beta catenin destruction complex (BCDC) since it has been shown to function at the convergence of signaling pathways initiated by growth factors, cytokines, Wnt ligands, sonic hedgehog, and G protein-coupled ligands [16]
Previous work from our laboratory and others have shown that exposure of cancer cells to chemotherapeutic agents induces cellular senescence [27] [28,29], suggesting that they may induce senescence-associated secretory phenotype (SASP)
Summary
Cellular senescence is a signal transduction program that leads to irreversible proliferation arrest in response to endogenous or exogenous stressors [1] It was initially considered as a manifestation of the overall decline in activity associated with aging of somatic cells [2], subsequent studies have shown that certain therapeutic agents induce a premature form of senescence [3,4,5], suggesting that this cellular process may be exploited for the development of approaches to suppress tumor growth. Due to the multitude of signaling pathways activated by SASP, a preferred molecular target must integrate the action of many if not all of them We reasoned that such target could be the beta catenin destruction complex (BCDC) since it has been shown to function at the convergence of signaling pathways initiated by growth factors, cytokines, Wnt ligands, sonic hedgehog, and G protein-coupled ligands [16]. The role of bcatenin or the associated destruction complex in mediating the action of SASP has not been described
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.
