Abstract
Bromodomain-containing protein 4 (BRD4) and PI3K-AKT are both important for renal cell carcinoma (RCC) development and progression. SF2523 is a BRD4 and PI3K-AKT dual inhibitor. The present study demonstrated that SF2523 was cytotoxic and anti-proliferative to established RCC cell lines (786-O and A498) and primary human RCC cells. SF2523 induced activation of caspase and apoptosis in RCC cells. Further, SF2523 disrupted RCC cell cycle progression and inhibited cell migration in vitro. At the signaling level, SF2523 in-activated PI3K-AKT-mTOR, and downregulated BRD4-dependent proteins, Bcl-2 and Myc, in RCC cells. Remarkably, SF2523 was more efficient than Wortmannin (the PI3K inhibitor) and JQ1 (the BRD4 specific inhibitor) in killing RCC cells. In vivo, SF2523 administration at well-tolerated doses suppressed 786-O xenograft tumor growth in severe combined immunodeficient (SCID) mice. Together, our results suggest that concurrent blockage of BRD4 and PI3K-AKT signalings by SF2523 efficiently inhibits RCC cell growth in vitro and in vivo.
Highlights
Total nephroureterectomy of early-stage and defined Renal cell carcinoma (RCC) tumor is only curable way clinically [1,2,3,4]
Our results suggest that concurrent blockage of Bromodomain-containing protein 4 (BRD4) and PI3K-AKT signalings by SF2523 efficiently inhibits renal cell carcinoma (RCC) cell growth in vitro and in vivo
In order to study the potential effect of SF2523 on RCC cells, the established 786-O RCC cells [10, 11, 14] were maintained in FBS-containing complete medium and were treated with SF2523 at different concentrations
Summary
Total nephroureterectomy of early-stage and defined Renal cell carcinoma (RCC) tumor is only curable way clinically [1,2,3,4]. RCC is typically diagnosed at advanced-stages with local invasion and/or systematic metastasis. The prognosis of these RCC patients is often extremely poor [3, 5,6,7,8]. During the process of mitosis, BRD4 binds directly to acetylatedhistones, which is required for maintaining chromatin structure in the daughter cells [15,16,17]. BRD4 is crucial for transcription machinery’s association with the specific chromatin regions to ensure the early re-initiation of transcription after mitosis [15,16,17]. BRD4 is shown to recruit P-TEFb (the positive transcription elongation factor b) and phosphorylate the RNA Pol II, allowing transcription elongation [15,16,17]
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