Targeting Aurora kinase-A downregulates cell proliferation and angiogenesis in neuroblastoma

Abstract

Purpose Aurora kinase A (AURKA) overexpression is associated with poor prognosis in neuroblastoma and has been described to upregulate VEGF in gastric cancer cells. However, the exact role of AURKA in the regulation of neuroblastoma tumorigenesis remains unknown. We hypothesize that AURKA-mediated stabilization of N-Myc may affect VEGF expression and angiogenesis in neuroblastoma. Therefore, we sought to determine whether inhibition of AURKA modulates neuroblastoma angiogenesis. Methods Cell viability and anchorage-independent growth were determined after silencing AURKA or after treatment with MLN8237, AURKA inhibitor. Immunofluorescence was used to determine N-Myc localization. Human umbilical vein endothelial cells (HUVECs) were used to assess angiogenesis in vitro. Real time-PCR and ELISA were performed to determine VEGF transcription and secretion, respectively. Results Knockdown of AURKA significantly reduced cell proliferation and inhibited anchorage-independent growth. It also decreased N-Myc protein levels and nuclear localization. AURKA inhibition also decreased HUVECs tubule formation along with VEGF transcription and secretion. Similarly, MLN8237 treatment decreased neuroblastoma tumorigenicity in vitro. Conclusions Our findings demonstrate that AURKA plays a critical role in neuroblastoma angiogenesis. AURKA regulates nuclear translocation of N-Myc in neuroblastoma cells, thus potentially affecting cell proliferation, anchorage-independent cell growth, and angiogenesis. Targeting AURKA might provide a novel therapeutic strategy in treating aggressive neuroblastomas.

Targeting Aurora Kinase A Inhibits Hypoxia-Mediated Neuroblastoma Tumor Progression

“…Given this, and our data demonstrating reduced in vitro neuroblastoma cell migration with inhibition of AURKA, we next attempted to identify the effect of silencing AURKA on FAK expression. We used stably-transfected AURKA-silenced BE(2)-C cells (shAURKA) established in our laboratory (2, 6). Under normoxic (O 2 , 21%) and hypoxic (O 2 , 1.1%) conditions, silencing of AURKA resulted in decreased expression of FAK and p-FAK, as compared to the control (shCON) (Figure 4).…”

“…Our laboratory has shown that it is involved in the regulation of angiogenesis and tumorigenicity in neuroblastoma (6)}. The function of AURKA under hypoxic conditions in neuroblastoma has not been extensively studied but others have demonstrated that the transcriptional regulation of AURKA is increased by both hypoxia and HIF-1α (7).…”

Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases

“…Hypoxia stimulates Aurora activity and consequently increases the malignant potential of hepatoma cells [35]. In addition, Aurora A inhibition has been observed to decrease the VEGF transcription and secretion in neuroblastoma cells and inhibit the HUVECs tubule formation [36]. So there might be a feedback loop of Aurora-VEGF-VEGFRs, we presumed that the mechanisms of Auroras and VEGFRs kinases dual inhibitors may be related with cutting off this feedback loop.…”

O papel da quinase Aurora A na biologia das células iniciadoras de turmor pulmonares com mutação em <i>KRAS</i>

“…Vários estudos mostram que a superexpressão de AURKA leva a má formação dos microtubulos, resultando em células aneuploides. Essa característica é muito encontrada em células tumorais, indicando que essa quinase pode ser um bom alvo terapêutico para o tratamento de diversos tipos de canceres (Meraldi et al, 2002;Romain et al, 2014). …”

“…O ensaio de colônia é um importante ensaio para avaliação da oncogenicidade in vitro e da viabilidade celular (Romain et al, 2014;Mahmoodi e Akrami, 2016). Para avaliar se a inibição farmacológica das quinases Aurora com AI II afeta a oncogenicidade das CITs oriundas da linhagem A549 e H358, nós realizamos ensaios 4.10.…”