Targeted Disruption of β-Arrestin 2-Mediated Signaling Pathways by Aptamer Chimeras Leads to Inhibition of Leukemic Cell Growth

Abstract

β-arrestins, ubiquitous cellular scaffolding proteins that act as signaling mediators of numerous critical cellular pathways, are attractive therapeutic targets because they promote tumorigenesis in several tumor models. However, targeting scaffolding proteins with traditional small molecule drugs has been challenging. Inhibition of β-arrestin 2 with a novel aptamer impedes multiple oncogenic signaling pathways simultaneously. Additionally, delivery of the β-arrestin 2-targeting aptamer into leukemia cells through coupling to a recently described cancer cell-specific delivery aptamer, inhibits multiple β-arrestin-mediated signaling pathways known to be required for chronic myelogenous leukemia (CML) disease progression, and impairs tumorigenic growth in CML patient samples. The ability to target scaffolding proteins such as β-arrestin 2 with RNA aptamers may prove beneficial as a therapeutic strategy.HighlightsAn RNA aptamer inhibits β-arrestin 2 activity.Inhibiting β-arrestin 2 impedes multiple tumorigenic pathways simultaneously.The therapeutic aptamer is delivered to cancer cells using a cell-specific DNA aptamer.Targeting β-arrestin 2 inhibits tumor progression in CML models and patient samples.

Aptamers: Uptake mechanisms and intracellular applications

“…The genetic ablation of β-arrestin 2 protects animal from the progression of myeloid leukemia [92]. For the therapeutic purpose, β-arrestin 2 specific RNA aptamers were isolated with counter SELEX against β-arrestin 1 [93].…”

“…This nucleolin-β-arrestin 2 aptamer chimeras allowed delivering intramers in chronic myelogenous leukemia cells without any viral vector or transfection agents. The nucleolin-β-arrestin 2 aptamer chimeras showed fully functional inhibition of β-arrestin 2 signaling cascades, showing down-regulation of β-catenin and Gli [93]. Consequently, the nucleolin-β-arrestin 2 aptamer chimeras inhibited the leukemia cell growth by colony forming assays [93].…”

“…The nucleolin-β-arrestin 2 aptamer chimeras showed fully functional inhibition of β-arrestin 2 signaling cascades, showing down-regulation of β-catenin and Gli [93]. Consequently, the nucleolin-β-arrestin 2 aptamer chimeras inhibited the leukemia cell growth by colony forming assays [93]. The anti-tumor effects were not determined in vivo.…”

In-Gel Imaging of RNA Processing Using Broccoli Reveals Optimal Aptamer Expression Strategies

“…These aptamers provide the opportunity to manipulate or investigate cellular function. For example, aptamers that bind and inhibit protein function have been developed and have the potential to serve as genetically encoded inhibitors of cellular signaling pathways (Kotula, et al, 2014; Seiwert, et al, 2000). Other aptamers have been developed that regulate splicing and other processes (Culler, et al, 2010; Weigand and Suess, 2007).…”

β-Arrestin2 mediates progression of murine primary myelofibrosis

“…are lacking, making it difficult to assess the full potential of β-arrestins as therapeutic targets. Kotula et al have effectively applied an aptamer chimera targeting βarr2 to CML cell lines and primary human samples, demonstrating that it is possible to effectively inhibit βarr2 in vitro (41). In this paper, our mouse model generated preliminary data supporting βarr2 as a therapeutic target in PMF and may provide impetus to invest efforts to develop tool compounds and ultimately therapeutic agents targeting βarr2.…”