Aurora Kinases in Cervical Cancer: Unraveling Oncogenic Mechanisms and Therapeutic Vulnerabilities

This phosphorylation event is tightly coordinated with INCENP binding and serves as a molecular switch for mitotic progression (72). In addition to phosphorylation, AURKB undergoes ubiquitination, which governs its proteasomal degradation during mitotic exit (73). Dysregulation of ubiquitin-mediated turnover leads to aberrant AURKB accumulation, contributing to chromosomal instability and aneuploidy (74). Understanding these intricate regulatory mechanisms is crucial for developing targeted therapies, exemplified by inhibitors such as ZM-447439 , which modulates Aurora kinase activity.

Emerging evidence also suggests crosstalk between phosphorylation and ubiquitination pathways, whereby sustained phosphorylation stabilizes AURKB and prolongs its mitotic activity in cancer cells (75). Collectively, these findings indicate that while AURKB isoform diversity is limited, structural integrity and post-translational modifications are central determinants of its oncogenic potential, particularly in malignancies characterized by mitotic checkpoint dysfunction.

Twu et al., 2009 conducted a comprehensive analysis of AURKA and AURKB kinase expression in normal cervical tissue, CIN3, and CC. Authors of this study have revealed an upregulation of both kinases in CIN3 and carcinoma compared to normal cervix, with a significant positive correlation between AURKA and AURKB expression, and higher AURKA overexpression observed in squamous cell carcinoma than in adenocarcinoma (57). These findings suggested that AURKA and AURKB overexpression represented an early molecular event in cervical epithelial transformation, implicating these kinases in the early pathogenesis of cervical dysplasia and malignant progression. Sun et al., 2015, explored the role of AURKA in CC by modulating its expression in cell lines. They found that AURKA overexpression promoted cell proliferation, G1/S transition, anti-apoptosis, and resistance to Taxol, while inhibition with VX-680 enhanced apoptosis and chemosensitivity. Clinical samples showed AURKA overexpression with an inverse correlation to pERK1/2, suggesting that AURKA drives CC progression and chemoresistance and may serve as a potential therapeutic target (76). Martin et al., 2017 evaluated the dual inhibitory effects of Alisertib, a selective Aurora kinase inhibitor, in preclinical models of HPV-driven CC. These investigators have demonstrated that Alisertib effectively inhibited both AURKA and AURKB in vivo, and that this dual inhibition induced antitumor efficacy and selectivity in CC models. Therapeutic action of Alisertib depends on mitotic progression and might not synergize with agents inducing a G2 DNA damage checkpoint, highlighting that simultaneous inhibition of AURKA and AURKB is essential for effective control of HPV-driven CC (77). Gabrielli et al., 2015 identified AURKA inhibition as lethal in the context of HPV E7 expression, demonstrating that the AURKA inhibitor Alisertib selectively induced apoptosis in HPV-driven CC cells. This effect was mediated by prolonged mitotic delay, resulting in decreased myeloid cell leukemia-1 (Mcl-1) and increased BCL-2-interacting modulator of cell death (BIM) levels, promoting apoptotic cell death. In vivo, Alisertib treatment led to tumor regression in HPV-positive xenografts and transgenic models, indicating that targeting AURKA can provide a potentially therapeutic strategy for HPV-driven CC (78). As listed in Table 2, foundation studies have shown that Aurora kinase inhibition in CC models disrupts critical pathways involved in cell proliferation, mitotic fidelity, and resistance to apoptosis.

List of Aurora kinase inhibitors in preclinical and clinical studies on Cervical Cancer (CC)

Taken together, the Aurora kinase family plays important roles in maintaining chromosomal stability through regulation of spindle assembly and cytokinesis, while its dysregulation, often in concert with HPV oncogenes and checkpoint failures, drives CC pathogenesis. Advancements in next-generation Aurora kinase inhibitors with improved specificity, lower toxicity, and combinatorial potential will highlight their promise as therapeutic agents for enhanced management of cervical malignancies. This ongoing pursuit of knowledge is supported by institutions dedicated to fundamental biological research, such as the RIKEN Center for Biosystems Dynamics Research .

Both AURKA and AURKB are frequently overexpressed in HPV-associated malignancies, including CC, with AURKB overexpression observed in approximately 40–60% of HPV-induced tumors (15). This upregulation is correlated with aggressive clinicopathologic features, including advanced tumor stage, increased lymph node metastasis, poor cellular differentiation, and reduced patient survival (16, 79). Mechanistically, E6 and E7 together promote AURKB dysregulation. HPV E6 directly interacts with AURKB through a unique α-helical region located immediately upstream of its PDZ-binding motif, which in high-risk genotypes such as HPV16 and HPV18 corresponds to the C-terminal sequences ETQV and ETQL, respectively (24).

HPV infection induces genomic instability, characterized by elevated phosphorylated AURKB (66). Depletion of E6 and E7 in CC cells resulted in reduced levels of both total and phosphorylated AURKB without significant changes in AURKB transcripts that implied a predominant post-transcriptional mode of viral regulation over kinase function (15). E6 and E7 also modulate the downstream signaling regulated by AURKB by abrogating p53- and pRb-mediated checkpoint control, thereby amplifying mitotic errors, chromosomal instability, and neoplastic transformation (80).

Mechanistically, HPV-mediated regulation of AURKB occur through post-transcriptional and checkpoint-associated mechanisms rather than direct transcriptional activation (15). High-risk HPV E6 physically associates with AURKB through a conserved α-helical domain proximal to its PDZ-binding motif, thereby influence the phosphorylation dynamics of AURKB, its kinase activity, and subcellular localization (81). Studies in HPV-positive cervical cancer cells have demonstrated that depletion of E6 and E7 reduces both total and phosphorylated AURKB protein levels without significantly altering AURKB transcript abundance (15, 24). This suggests that viral oncoproteins regulate AURKB through post-translational mechanisms involving protein stabilization and modulation of kinase activation rather than transcriptional induction.

AURKB catalytic activity is tightly controlled through autophosphorylation of Thr232 residue, which is facilitated by the interaction with INCENP and checkpoint-dependent phosphorylation. These post-translational modifications regulate centromeric localization and chromosomal passenger complex functionality (66). Studies have demonstrated that HPV E6 binding alter AURKB dynamics directly; but the other viral protein ie., E7 contributes indirectly to the AURKB activation by establishing a permissive mitotic environment characterized by checkpoint dysfunction (Figure 3) (24).

Mechanism of HPV E6/E7-mediated AURKB dysregulation and oncogenic progression in cervical cancer

This section describes the role of HPV E6 and E7 oncoproteins in cervical cancer progression through disruption of p53 and pRb tumor suppressor pathways and dysregulation of AURKB signaling. E6 promotes p53 degradation via E6AP-mediated ubiquitination and stabilizes AURKB, leading to abnormal mitotic signaling and chromosomal instability. E7 inactivates pRb, releasing E2F transcription factors and enhancing expression of mitotic regulators including AURKB and AURKA. These combined effects promote genomic instability, uncontrolled proliferation, enhanced cell survival, and malignant progression in cervical cancer.

HPV E6 promotes proteasomal degradation of p53 through E6AP-mediated ubiquitination, while E7 functionally inactivates pRb, releasing E2F transcription factors and overriding G1/S checkpoint control (82). Furthermore, disruption of spindle assembly checkpoint fidelity enhances dependence on AURKB-mediated mitotic signaling, promoting chromosomal instability, polyploidy, and malignant progression (83). Therefore, HPV-driven AURKB activation represents a multifactorial process involving direct viral-host protein interactions, post-translational kinase regulation, and checkpoint deregulation, all of which act synergistically to sustain cervical carcinogenesis.