Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer

Abstract

Identifying novel actionable factors that critically contribute to tumorigenesis is essential in ovarian cancer, an aggressive and disseminative tumor, with limited therapeutic options available. Here we show that Aurora Borealis (BORA), a mitotic protein that plays a key role in activating the master mitotic kinase polo-like kinase 1 (PLK1), has an oncogenic role in ovarian cancer. Gain and loss of function assays on mouse models and ex vivo patient-derived ascites cultures revealed an oncogenic role of BORA in tumor development and a transcriptome-analysis in clinically representative models depicted BORA's role in survival, dissemination and inflammatory cancer related-pathways. Importantly, combinatory treatments of FDA-approved inhibitors against oncogenic downstream effectors of BORA displayed synergistic effect in ovarian cancer models, offering promising therapeutic value. Altogether, our findings uncovered for the first time a critical role of BORA in the viability of human cancer cells providing potential novel therapeutic opportunities for ovarian cancer management.Cancers 2020, 12, 886 2 of 25 in cell cycle division. Nevertheless, even though BORA depletion has been reported to reduce the activity of PLK1 kinase, our understanding of its relevance in cancer is still very limited and there is no comprehensive study that defines the downstream biological consequences of BORA modulation in cancer. Recent evidence has shown that BORA is overexpressed in various tumors such breast, lung, and gastric adenocarcinomas and might serve as a prognostic biomarker [8].Ovarian cancer (OC), the most lethal gynecologic malignancy, is frequently diagnosed at advanced stages with disseminated disease, which limits the therapeutic options [9]. Despite improved cytoreductive surgical approaches and chemotherapy-based regimens, the survival of OC patients has remained largely unchanged during the last two decades [10,11]. Recent advances in cancer genomics have revealed that OC is molecularly a very heterogeneous disease, with extensive genomic instability, copy-number variations and defects in the homologous recombination repair pathway [12]. These genomic aberrations contribute to the development of tumor resistance, hampering effective treatment and ultimately causing disease recurrence [13], but also offer novel potential actionable vulnerabilities that can enhance the effectiveness of existing therapies.Molecular targeted therapies have been implemented routinely into the clinics changing OC management with the inclusion of anti-angiogenic compounds (i.e., monoclonal antibodies such Bevacizumab) [14,15] and poly ADP-ribose polymerases (PARP) inhibitors (i.e., Olaparib or Rucaparib) for breast-cancer (BRCA)-mutated carriers and BRCAness phenotype patients [16,17]. Synthetic lethality produced by PARP inhibitors enhances the therapeutic window after chemotherapy in recurrent platinum-sensitive OC subjects [18]. Nonetheless, it is effective in only a subset of patients, highlighting the urgent clinical need of searching...

MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation

“…As aforementioned, PLK1 has been implicated in OC progression as well [9]. Likewise, activation of PLK1 was responsible for the oncogenic role of Aurora Borealis in OC [29]. PLK1 inhibitors have seen potentials in the clinical management of cancers by blocking cancer cell mitosis and triggering cell apoptosis [30].…”

Aurora A kinase activation: Different means to different ends

“…However, this form of AURKA is readily detected in melanoma cells bearing PP6 mutations, which gives rise to pathological chromosome instability and DNA damage ( Hammond et al, 2013 ). Bora is overexpressed in multiple cancer types, including ovarian cancer, where it plays a pro-oncogenic role ( Parrilla et al, 2020 ), and there is significant evidence for ROS signaling, which is involved in centrosomal AURKA activation by Cep192, contributing to a number of disease states. Finally, AURKA itself is overexpressed in numerous cancers associated with drug resistance and poor patient outcome.…”

The Polo-like kinase 1 inhibitor onvansertib represents a relevant treatment for head and neck squamous cell carcinoma resistant to cisplatin and radiotherapy

“…Dysfunction of these interactions could be associated with the overexpression of Plk1 and its capacity to induce tumor development. Bora/Aurora A activates Plk1 at mitosis entry and have an essential role in ovarian tumor development 32 . E2F and FoxM1, two transcription factors regulate Plk1 expression 33 , 34 , thus they could be closely related to Plk1-dependent tumor development 35 .…”