Search Results (90)

Despite a thorough understanding of the structure of human papillomavirus (HPV) and its genotypic variations (high-risk and low-risk variants), the mechanisms underlying HPV-induced cervical cancer (CC) pathogenesis and the molecular signatures of drug resistance remain to be fully understood. Accumulating evidence has shown the involvement of kinase targets in the induction of drug resistance in high-risk (HR) HPV-CC. Molecularly, the genome of high-risk HPV is reported to control the expression of host kinases. In particular, Aurora kinases A, B, and C (ARKA, ARKB, and ARKC), phosphotidylinositol–trisphosphate kinase (PI3K)-Akt, and Glycogen synthase kinase3-α/β (GSK3 α/β) promote the transformation of infected cells, and also enhance the resistance of cells to various chemotherapeutic agents such as nelfinavir and cisplatin. However, the precise mechanisms through which HPV activates these kinases are yet to be fully elucidated. Furthermore, there is still ambiguity surrounding whether targeting HPV-induced kinases along with HPV-targeted therapies (such as phytopharmaceuticals and PROTAC/CRISPR-CAS-based systems) synergistically inhibit cervical tumor growth. Given the critical role of kinases in the pathogenesis and treatment of CC, a comprehensive review of current evidence is warranted. This review aims to provide key insights into the mechanisms of HPV-induced CC development, the involvement of kinases in drug resistance induction, and the rationale for combination therapies to improve clinical outcomes. Full article

Objectives: Although Aurora kinase A (AURKA) expression has been investigated in many cancer types, studies focusing on its role in hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) are limited. In this study, we examined the activity of AURKA and its substrates (PLK1, P53, and BRCA1) in HBV-HCC and cryptogenic hepatocellular carcinoma (Cr-HCC) cases. Methods: The study groups consisted of HBV-HCC, Cr-HCC, and healthy liver tissue cases. AURKA copy number variation (CNV) was analyzed using molecular methods. AURKA expression was evaluated by molecular and immunohistochemical (IHC) methods. AURKA substrates P53^Ser315, PLK1^Thr210, and BRCA1 were also analyzed by IHC. Results: There was no increase in AURKA gene copy number among the groups (2^−∆∆Ct < 2). AURKA level was significantly increased in both test groups (p < 0.001). At the protein level, AURKA was significantly higher in both cancer groups compared to the control group (p < 0.001). Phospho-P53^Ser315 levels were significantly higher in both HBV-HCC and Cr-HCC groups compared to the control group (p = 0.002 and p < 0.001, respectively). Cr-HCC cases also showed significantly higher levels compared to HBV-HCC (p = 0.025). For phospho-PLK1^Thr210, Cr-HCC cases showed statistically higher expression compared to both the control group and HBV-HCC cases (p = 0.001). Full article

Background: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response. Methods: We performed a sex-stratified analysis of CGGA (Chinese Glioma Genome Atlas) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM). Using the 3PodR framework, we integrated differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing. Results: These comparisons provide a proxy for biological processes underlying malignant transformation. In LGG vs. HGG, 973 significantly differentially expressed genes (DEGs) were identified in females and 1236 in males, with 15.5% and 33.5% unique to each sex, respectively. In LGG vs. GBM, 2011 DEGs were identified in females and 2537 in males, with 12.6% and 30.7% being unique. Gene-level contrasts included GLI1 upregulation in males and downregulation in females, GCGR upregulation in males, MYOD1 upregulation in females, and HIST1H2BH downregulation in males. Additional top DEGs included PRLHR, DGKK, DNMBP-AS1, HOXA9, CTB-1I21.1, RP11-47I22.1, HPSE2, SAA1, DLK1, H19, PLA2G2A, and PI3. In both sexes, LGG–HGG and LGG–GBM grade comparisons converged on neuronal and synaptic programs, with enrichment of glutamatergic receptor genes and postsynaptic modules, including GRIN2B, GRIN2A, GRIN2C, GRIN1, and CHRNA7. In contrast, collateral pathways diverged by sex: females showed downregulation of mitotic and chromosome-segregation programs, whereas males showed reduction of extracellular matrix and immune-interaction pathways. Perturbagen analysis nominated signature-reversing compounds across sexes, including histone deacetylase inhibitors, Aurora kinase inhibitors, microtubule-targeting agents such as vindesine, and multi-kinase inhibitors targeting VEGFR, PDGFR, FLT3, PI3K, and MTOR. Conclusions: Glioma grade comparisons reveal a shared neuronal–synaptic program accompanied by sex-specific transcriptional remodeling. These findings support sex-aware therapeutic strategies that pair modulation of neuron–glioma coupling with chromatin- or receptor tyrosine kinase/angiogenic-targeted agents, and they nominate biomarkers such as GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH for near-term validation. Full article

Background/Objectives: Doxorubicin (DOXO) is effective against various types of cancer; however, it is associated with hepatotoxicity that may eventually lead to liver fibrosis, limiting its clinical use. Aurora kinase A (AURKA) has emerged as a crucial regulator of essential cellular processes and a promising target to overcome tumors resistant to some anticancer drugs, including DOXO. However, the potential beneficial effect of targeting AURKA on DOXO-induced toxicities has not been explored yet. Therefore, the current study aimed to explore the potential protective effect of the AURKA-selective inhibitor alisertib on DOXO-induced hepatotoxicity in mice and address the possible underlying mechanism. Methods: Mice were treated with alisertib (10 and 20 mg/kg) daily for five consecutive days and challenged with DOXO (20 mg/kg, i.p.) once on day two. Results: Our findings revealed that alisertib significantly reduced biomarkers of liver dysfunction and oxidative stress elevated by the DOXO challenge. Interestingly, alisertib suppressed DOXO-induced IL-17A upsurge along with NF-κB and STAT3 activation. Alisertib also suppressed the upregulated expression of HIF-1α and VEGF-A as well as PERK activation associated with the DOXO challenge. Moreover, alisertib counteracted DOXO-induced TGF-β1 and α-SMA overexpression in the liver. These beneficial effects of alisertib were further reflected in the histopathological findings, which indicated the ability of alisertib to ameliorate DOXO-induced hepatic necroinflammation and fibrosis. Conclusions: Alisertib mitigates DOXO-induced hepatotoxicity in mice via targeting the IL-17A/NF-κB and IL-17A/STAT3/HIF-1α/VEGF-A signaling pathways, attenuating oxidative stress, inflammation, ER stress, and fibrosis. Full article

Aurora kinase B (AURKB), a serine/threonine protein kinase, is essential for accurate chromosome segregation and cytokinesis during mitosis. Dysregulation of AURKB, often characterized by its overexpression, has been implicated in various malignancies, including breast cancer. However, the mechanisms governing its dysregulation remain incompletely understood. Here, we identify a pivotal role for the MOF/MSL complex—which includes the histone acetyltransferase MOF (KAT8)—in modulating AURKB stability through acetylation at lysine 215 (K215). This post-translational modification inhibits AURKB ubiquitination, thereby stabilizing its protein levels. MOF/MSL-mediated AURKB stabilization promotes the proper assembly of the chromosomal passenger complex (CPC), ensuring mitotic fidelity. Notably, inhibition of MOF reduces AURKB K215 acetylation, leading to decreased AURKB expression and activity. Consequently, this downregulation suppresses expression of the downstream oncogene c-MYC, ultimately attenuating the malignant proliferation of breast cancer cells. Collectively, our findings reveal a novel mechanism by which lysine acetylation regulates AURKB stability, highlight the significance of the MOF-AURKB-c-MYC axis in breast cancer progression, and suggest potential therapeutic strategies targeting this pathway in clinical settings. Full article

Background: The treatment landscape for multiple myeloma (MM) has significantly evolved in recent decades with novel therapies like proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. However, MM remains incurable, necessitating new pharmacological strategies. Mitotic kinases, such as Aurora proteins, have emerged as potential targets. Selective inhibitors of Aurora A and B,- alisertib (MLN8237) and barasertib (AZD1152), respectively, have shown anti-myeloma activity in preclinical studies, with alisertib demonstrating modest efficacy in early clinical trials. Methods and Results: This study investigated the mechanisms of action of alisertib and barasertib and their combination with antitumor agents in a panel of five MM cells lines. Both drugs induced cell cycle arrest phase and abnormal nuclear morphologies. Alisertib caused prolonged mitotic arrest, whereas barasertib induced transient arrest, both resulting in the activation of mitotic catastrophe. These findings revealed three potential outcomes: cell death, senescence, or polyploidy. High mitochondrial reactive oxygen species (mROS) were identified as possible drivers of cell death. Caspase inhibition reduced caspase-3 activation but did not prevent cell death. Interestingly, alisertib at low doses remained toxic to Bax/Bak^DKO cells, although mitochondrial potential disruption and cytochrome c release were observed. Sequential combinations of high-dose Aurora kinase inhibitors with BH3-mimetics, and in specific cases with panobinostat, showed a synergistic effect. Conversely, the simultaneous combination of alisertib and barasertib showed mostly antagonistic effects. Conclusions: Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules. Full article

Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive pediatric soft-tissue sarcoma driven by PAX3/7-FOXO1 fusion proteins. Despite intensive multimodal therapy, outcomes remain poor for patients with fusion-positive ARMS. This review integrates recent advances in the molecular pathogenesis of ARMS, highlighting key diagnostic and therapeutic targets. We discuss the central role of fusion proteins in transcriptional reprogramming, impaired myogenic differentiation, and super-enhancer activation. Emerging biomarkers (YAP, TFAP2B, P-cadherin) and oncogenic kinases (Aurora A, CDK4, PLK1) are evaluated alongside receptor tyrosine kinases (FGFR, MET) and transcription factors involved in metabolic rewiring (FOXF1, ETS1). Additionally, we examine immunotherapeutic strategies, epigenetic modifiers, and noncoding RNAs as potential therapeutic avenues. Together, these insights provide a comprehensive framework for developing biomarker-guided, multi-targeted therapies to improve outcomes in ARMS. Full article

Epithelial ovarian cancer (EOC) exhibits a unique mode of metastasis, involving spheroid formation in the peritoneum. Our research on EOC spheroid cell biology has provided valuable insights into the signaling plasticity associated with metastasis. We speculate that EOC cells modify their biology between tumour and spheroid states during cancer dormancy, although the specific mechanisms underlying this transition remain unknown. Here, we present novel findings from direct comparisons between cultured EOC spheroids and organoids. Our results indicated that AMP-activated protein kinase (AMPK) activity was significantly upregulated and protein kinase B (Akt) was downregulated in EOC spheroids compared to organoids, suggesting a clear differential phenotype. Through RNA sequencing analysis, we further supported these phenotypic differences and highlighted the significance of cell cycle regulation in organoids. By inhibiting the G2/M checkpoint via kinase inhibitors, we confirmed that this pathway is essential for organoids. Interestingly, our results suggest that specifically targeting aurora kinase A (AURKA) may represent a promising therapeutic strategy since our cells were equally sensitive to Alisertib treatment as both spheroids and organoids. Our findings emphasize the importance of studying cellular adaptations of EOC cells, as there may be different therapeutic targets depending on the step of EOC disease progression. Full article

Background/Objectives: Breast cancer (BC) remains one of the most prevalent and deadly cancers worldwide, with limited access to advanced treatments in developing regions. There is a critical need for novel therapies with unique mechanisms of action, especially to overcome resistance to conventional platinum-based drugs. This study investigates the anticancer potential of the ruthenium complex Bis(quinolin-8-olato)bis(triphenylphosphine)ruthenium(II) (Ru(quin)₂) in ER-positive (T47D) and triple-negative (MDA-MB-231) BC cell lines. Results: Ru(quin)₂ demonstrated dose-dependent cytotoxicity, with IC50 values of 48.3 μM in T47D cells and 45.5 μM in MDA-MB-231 cells. Its cytotoxic effects are primarily driven by apoptosis, as shown by increased BAX expression, enhanced caspase-3 activity, reduced Aurora B kinase levels, and elevated histone release. Ru(quin)₂ also induced autophagy, evidenced by LC3-I to LC3-II conversion and reduced SQSTM1, partially mediated through MAPK signaling. Furthermore, Ru(quin)₂ induced G0/G1 cell cycle arrest by downregulating cyclin D1, CDK4, and CDK6, alongside upregulation of the CDK inhibitor p21. Conclusions: Ru(quin)₂ emerges as a potent candidate for BC treatment, with multiple mechanisms of action involving apoptosis, autophagy, and cell cycle arrest. Further studies are warranted to elucidate its detailed molecular mechanisms and evaluate its therapeutic potential in vivo, moving toward clinical applications for both ER-positive and triple-negative BC management. Full article

Background: Aurora kinase B (AurB) is a pivotal regulator of mitosis, making it a compelling target for cancer therapy. Despite significant advances in protein kinase inhibitor development, there are currently no AurB inhibitors readily available for therapeutic use. Methods: This study introduces a machine learning-assisted drug repurposing framework integrating quantitative structure-activity relationship (QSAR) modeling, molecular fingerprints-based classification, molecular docking, and molecular dynamics (MD) simulations. Using this pipeline, we analyzed 4680 investigational and approved drugs from DrugBank database. Results: The machine learning models trained for drug repurposing showed satisfying performance and yielded the identification of saredutant, montelukast, and canertinib as potential AurB inhibitors. The candidates demonstrated strong binding energies, key molecular interactions with critical residues (e.g., Phe88, Glu161), and stable MD trajectories, particularly saredutant, a neurokinin-2 (NK2) antagonist. Conclusions: Beyond identifying potential AurB inhibitors, this study highlights an integrated methodology that can be applied to other challenging drug targets. Full article

Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and Results: Alisertib, an AK-A inhibitor, has anti-tumor activity in relapsed/refractory (r/r) MCL patients. We evaluated alisertib plus ibrutinib in MCL to abrogate ibrutinib resistance. Alisertib plus ibrutinib was therapeutically synergistic on both Granta-519 insensitive to ibrutinib and JeKo-1 cells sensitive to ibrutinib. Alisertib decreased PI-3K, BTK, p38, HCK, and RSK kinases, indicative of its multipotent effect on cellular proliferation and growth. A mouse xenograft model of Granta-519 demonstrated that alisertib plus ibrutinib had a comparable anti-tumor response to ibrutinib plus rituximab. However, alisertib plus ibrutinib plus rituximab demonstrated significantly stronger tumor growth inhibition than the doublets. Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL. Full article

Survivin is known for its dual biological role in apoptosis inhibition and mitotic progression. In addition to its being part of the chromosomal passenger complex (CPC), recent findings suggest additional roles for Survivin in the DNA damage response, further contributing to therapy resistance. In this study, we investigated the role of Survivin and the CPC proteins in the cellular response to irradiation with a focus on DNA replication processes. As is known, ionizing radiation leads to an increased expression of Survivin and its accumulation in nuclear foci, which we now know to be specifically localized to centromeric heterochromatin. The depletion of Survivin and Aurora B increases the DNA damage marker γH2AX, indicative of an impaired repair capacity. The presence of Survivin and the CPC in nuclear foci that we already identified during the S phase co-localize with the proliferating cell nuclear antigen (PCNA), further implying a potential role during replication. Indeed, Survivin knockdown reduced replication fork speed as assessed via DNA fiber assays. Mechanistically, we identified a PIP-box motif in INCENP mediating the interaction with PCNA to assist in managing damage-induced replication stress. Survivin depletion forces cells to undergo unphysiological genome replication via mitotic DNA synthesis (MiDAS), resulting in chromosome breaks. Finally, we revealed that Aurora B kinase liberates Pol η by phosphorylating polymerase delta-interacting protein 2 (POLDIP2) to resume the replication of damaged sites via translesion synthesis. In this study, we assigned a direct function to the CPC in the transition from stalled replication forks to translesion synthesis, further emphasizing the ubiquitous overexpression of Survivin particularly in tumors. This study, for the first time, assigns a direct function to the chromosomal passenger complex, CPC, including Survivin, Aurora B kinase, Borealin, and INCENP, in the transition from stalled replication forks (involving PCNA binding) to translesion synthesis (liberating Pol η by phosphorylating POLDIP2), and thus in maintaining genomic integrity. Full article

The centrosome of the amoebozoan model Dictyostelium discoideum provides the best-established model for an acentriolar centrosome outside the Opisthokonta. Dictyostelium exhibits an unusual centrosome cycle, in which duplication is initiated only at the G2/M transition and occurs entirely during the M phase. Little is known about the role of conserved centrosomal kinases in this process. Therefore, we have generated knock-in strains for Aurora (AurK), CDK1, cyclin B, Nek2, and Plk, replacing the endogenous genes with constructs expressing the respective green fluorescent Neon fusion proteins, driven by the endogenous promoters, and studied their behavior in living cells. Our results show that CDK1 and cyclin B arrive at the centrosome first, already during G2, followed by Plk, Nek2, and AurK. Furthermore, CDK1/cyclin B and AurK were dynamically localized at kinetochores, and AurK in addition at nucleoli. The putative roles of all four kinases in centrosome duplication, mitosis, cytokinesis, and nucleolar dynamics are discussed. Full article

Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA’s role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy. Full article

Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness. Full article