Anti-survivin effect of the small molecule inhibitor YM155 in RCC cells is mediated by time-dependent inhibition of the NF-κB pathway

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.

Survivin promotes a glycolytic switch in CD4+ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis

“…In the light of our findings, unexpected translocation of TF SP1, ILF/NF110, and NF-κB heterodimers during YM155 treatment 74 , 75 could be explained by previously unappreciated survivin binding to chromatin as a part of large TF complexes described by our studies. Concordant with Sim et al., 76 we observed a significant upregulation of FOXO1 and CYLD in YM155 treated CD4 + cells, which could be explained by survivin binding to RE connected to these genes. Thus, the results of this study support survivin-targeting specificity of YM155, but this assumption needs further investigations.…”

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

“…The proinflammatory effect of the HMGB1-RAGE axis is significantly associated with the NF-κB pathway, which involves extracellular signal-regulated kinase 1 and 2 (ERK1/2), and p38 MAPK. Then, activated NF-κB translocates to the nucleus and interacts with DNA as a p65/p50 heterodimer, which enhances proinflammatory cytokine expression [46][47][48]. Although the role of the HMGB1-RAGE axis in cancer is not completely clear, HMGB1 is critical for directly activating RAGE or activating peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway, and inhibiting HMGB1-RAGE activation, which might be a beneficial cancer therapeutic strategy [49].…”

Survivin prevents the Polycomb Repressor Complex 2 from methylating Histone 3 lysine 27

“…24 YM155 also targets the transcription factor ILF/NF110 25 it downregulates ID1 expression but stimulates CYLD and FOXO1. 26 Nuclear translocation of NF-kB heterodimeres (p65/p50) was also disturbed after YM155 treatment. 27 Despite of the above mentioned side effects of YM155, survivin is suppressed specifically, independently from closely linked proteins.…”