Abstract
Constitutive activation of the NF-κB signaling cascade is associated with tumourigenesis and poor prognosis in many human cancers including RCC. YM155, a small molecule inhibitor of survivin, was previously shown to potently inhibit the viability of immortalized and patient derived renal cell carcinoma (RCC) cell lines. Here we investigated the role of NF-κB signaling to the anti-cancer properties of YM155 in RCC786.0 cells. YM155 diminished nuclear levels of p65 and phosphorylated p65 and attenuated the transcriptional competencies of the p65/p50 heterodimers. Accordingly, we found that YM155 diminished the transcription of NF-κB target gene survivin. Events that led to the interception of the nuclear translocation of p65/p50 were the activation of the deubiquinating enzyme CYLD by YM155, which led to the inhibition of IKKβ, stabilization of IκBα and retention of NF-κB heterodimers in the cytosol. Importantly, the suppressive effects of YM155 were time-dependent and observed at the 24 h time point, and not earlier. TNF-α, a stimulator of NF-κB signaling did not affect its inhibitory properties. The ability of YM155 to intercept a major transcriptional pathway like NF-κB, would have important ramifications on the pharmacodynamics effects elicited by this unusual molecule.
Highlights
Renal cell carcinoma (RCC) is the most lethal urologic malignancy
We reconfirmed our earlier findings that YM155 potently inhibited the proliferation of RCC7860.0 cells at nanomolar concentrations (Supplementary Figure 1: DRC)
To determine if YM155 could have intercepted these upstream events which crucially determine the sequesteration of NF-κB dimers within the cytosol, we examined the levels of IKKβ, phospho-IKKβ, IκBα phospho-IκBα and CYLD in RCC786.0 cells after treatment with YM155 (40 nM) for 24 h
Summary
Renal cell carcinoma (RCC) is the most lethal urologic malignancy. Approximately one in three patients with RCC exhibit visceral metastasis[1] at the time of diagnosis while half of the remaining patients would eventually develop distant metastases after surgery[2]. We followed up on three genes that were relevant to RCC pathogenesis and have not been implicated as targets of YM155, namely CYLD (cylindromatosis, a deubiquitinating enzyme that negatively regulates NF-κB transcription activity), FOXO1 (a tumour suppressor that mediates cell cycle arrest and promotes apoptosis) and ID1 (an inhibitor of DNA binding that suppresses transcriptional activation of HLH proteins which leads to tumour growth and angiogenesis)[13]. Collateral evidence from both mRNA and protein analyses revealed that YM155 downregulated ID1 expression but stimulated CYLD and FOXO1. We demonstrate that YM155 caused a time dependent attenuation of NF-κB signaling in RCC786.0 cells, primarily by intercepting the nuclear translocation of the p65 subunit and curtailing its transcriptional activity
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