mln-8237 and Carcinoma--Renal-Cell

Renal cell carcinoma (RCC) is a common malignant tumor in the world. Histologically, most of RCC is classified as clear cell renal cell carcinoma (ccRCC), which is the most prevalent subtype. The overall survival of patients with ccRCC is poor, thus it is urgent to further explore its mechanism and target. S-phase kinase-associated protein 2 (SKP2) is overexpressed in a variety of human cancers and is associated with poor prognosis by enhancing tumor progression. However, it is unclear whether or how SKP2 is involved in ccRCC progression. Here, we reported that overexpression of SKP2 enhanced cell proliferation of ccRCC, while SKP2 depletion exhibited the opposite effect. Bioinformatic analyses found that SKP2 was positively correlated with Aurora-A (Aur-A) in ccRCC. The protein and mRNA levels of SKP2 were elevated or reduced by Aur-A overexpression or silencing, respectively. It was further found that Aur-A caused an increase phosphorylation of FOXO3A, which is a negatively transcription factor for SKP2. Interestingly, SKP2 mediated ubiquitylation and degradation of FOXO3A depend on the kinase activity of Aur-A. The combination of Aur-A inhibitor MLN8237 and SKP2 inhibitor SZL P1-41 showed a synergistic tumor growth inhibition in vivo and in vitro of ccRCC models. Thus, our data reveal that Aurora-A/FOXO3A/SKP2 axis promotes tumor progression in ccRCC, and the double inhibition of SKP2 and Aur-A shows significant synergistic effect, which indicates a potential new therapeutic strategy for ccRCC.

Topics: Aurora Kinase A; Azepines; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Forkhead Box Protein O3; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyrimidines; S-Phase Kinase-Associated Proteins; Signal Transduction

The majority of molecular targets of anticancer agents are limited to a subset of patients, and therefore identification of more specific biomarkers that can be used to improve clinical outcomes is of increasing interest. The present study showed that von Hippel‑Lindau tumor suppressor (VHL) tumor‑suppressor activity may influence the therapeutic response to Aurora kinase A (AURKA) inhibitors in human renal cell carcinoma (RCC). VHL protein (pVHL) expression was evaluated by immunoblotting in the human RCC cell lines CAKI, ACHN, 786‑O, 769‑P and A498. The anti‑tumor activities of alisertib, an AURKA‑specific chemical inhibitor, were detected by Cell Counting Kit‑8 assay in vitro and mouse xenograft model in vivo. Additionally, the VHL‑mediated anti‑tumor activity was assessed in 769‑P and CAKI cells via the loss or gain of VHL. The results revealed that VHL‑deficient 786‑O, 769‑P and A498 cells were sensitive to alisertib. By contrast, alisertib‑resistant CAKI and ACHN cells expressed the wild type VHL gene. In addition, rescue or knockdown of VHL was observed to increase or decrease alisertib anti‑proliferation activity, respectively, in RCC cells. The inverse correlation between the VHL gene expression profile and alisertib sensitivity was further confirmed in human cancer xenografts models. Taken together, these results suggested that VHL loss could potentially serve as a biomarker for predicting the efficacy of AURKA inhibitors.

Topics: Animals; Aurora Kinase A; Azepines; Carcinoma, Renal Cell; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Kinase Inhibitors; Pyrimidines; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays