This review synthesizes available evidence indicating that several KIFs, specifically KIF4A, KIF14, KIF20A, and KIFC1, function as key oncogenic regulators and represent important prognostic biomarkers and therapeutic targets in bladder cancer.
Abstract
Bladder cancer is a long‐standing clinical issue, with frequent recurrence and continuously disappointing results in patients, so that therapeutic development is primarily reliant on delineating the original molecular defects. Increasing interest has turned to the Kinesin Superfamily Proteins (KIFs), basic molecular motors that move along microtubule rails, and are now emerging as important key oncogenic derivers in bladder cancer pathogenesis. This review synthesizes available evidence indicating that several KIFs, specifically KIF4A, KIF14, KIF20A, and KIFC1, function as key oncogenic regulators and represent important prognostic biomarkers and therapeutic targets in bladder cancer. When KIF expression or activity is disrupted, it provides mechanical and signaling support for all the cancer hallmarks, facilitating cellular proliferation, invasion, metastasis, and resistance to highly effective cell death. Its oncogenic activity is generally facilitated by the activation of principal signaling pathways. A remarkable proportion of certain KIF isoforms are commonly overexpressed in cancer, and the scale of such overexpression increases with the severity of adverse clinical predictors, such as increasing disease stage, and patient survival worsens. This nuanced molecular image renders KIFs so highly promising targets for therapeutic intervention and prognostic stratification, and initial exploration of kinesin inhibitors is encouraging to abate chemoresistance, aside from optimizing the efficacy of current immunotherapies. Uncovering modalities that exploit the aggressive bladder cancer cell dependence on KIF motor activity is a highly promising path to clinical application.
Drug resistance in cancer remains a major barrier to durable therapeutic benefits and limits the effectiveness of chemotherapy, targeted therapy, and combination treatment in multiple malignancies. Increasing evidence indicates that specific kinesin superfamily proteins contribute to tumor adaptation and therapeutic response in a context-dependent manner through their roles in mitotic regulation, intracellular transport, and stress-response pathways. Aberrant expression of multiple kinesin family members has been documented across diverse cancers and is frequently associated with aggressive clinicopathological features, poor prognosis, and resistance to treatment. However, expression alterations alone do not establish functional dependency, and mechanistic validation is required to distinguish true resistance drivers from adaptive tumor states. In this review, we summarize the classification, biological functions, and abnormal expression patterns of kinesins in cancer; discuss the major mechanisms through which they contribute to drug resistance; and examine strategies for targeting kinesins, including natural-product-derived direct inhibitors, small-molecule inhibitor development, rational combination approaches, and structure-guided and computational optimization strategies. We also evaluate the biomarker potential of kinesin dysregulation and the value of advanced preclinical models for mechanistic and translational investigations. Finally, we highlight the major challenges that hinder clinical translation, including target specificity, compensatory resistance, insufficient biomarker validation, and tumor heterogeneity. Future progress will require integration of functional genomics, multiomics profiling, and mechanism-guided therapeutic strategies to determine when kinesin inhibition represents a clinically actionable approach for resistant malignancies.
This review underscores the transformative potential of molecular profiling and FGFR-targeted therapies in the evolving management of bladder cancer, with special attention given to the fibroblast growth factor receptor (FGFR) signaling pathway.
Nandita Yadav, Nihar Ranjan Sarmah, Ketan J. Purohit et al.· Current Pharmacogenomics and...· 0 citations
Colorectal cancer (CRC) remains a leading cause of cancer mortality with few effective targeted therapies. Kinesin family member 11 (KIF11), a motor protein essential for mitotic spindle assembly, is frequently overexpressed in multiple cancers. We hypothesized that nitidine chloride (NC), a natural benzophenanthridine alkaloid with documented anti-tumor activity, might suppress CRC by targeting KIF11.Molecular docking predicted a strong interaction between NC and KIF11 (− 9.0 kcal/mol). RNA sequencing, quantitative RT-PCR, and immunohistochemistry confirmed that NC treatment markedly downregulated KIF11 expression. Meta-analysis across public datasets showed consistent KIF11 mRNA overexpression in CRC (standardized mean difference [SMD] = 1.33; AUC = 0.87), while in-house immunohistochemistry on 416 clinical specimens demonstrated even stronger protein-level elevation (AUC = 0.99) that correlated with larger tumor size and deeper invasion. Single-cell RNA sequencing and spatial transcriptomics further revealed that KIF11 is preferentially expressed in proliferative malignant epithelial cells. Through CRISPR-based knockout screening and lentiviral silencing, KIF11 depletion impaired the growth or viability of the examined CRC cell models. Public ChIP-seq data suggested RAD21 occupancy near the KIF11 regulatory region, whereas reciprocal co-immunoprecipitation supported an association between the RAD21 and KIF11 proteins. Among genes co-expressed with KIF11,a pronounced enrichment was observed in pathways governing cell-cycle progression. Following KIF11 knockdown, transcriptomic profiling showed reduced expression across cell-cycle, DNA-replication, and chromatin-cohesion programs, alongside a reciprocal increase in amino-acid metabolism and stress-response genes. At the functional level, KIF11 depletion suppressed cell proliferation and induced G2/M-phase arrest. Taken together, these in vitro and limited xenograft data indicate that NC restrains CRC growth chiefly through the RAD21–KIF11 axis; KIF11 represents a promising preclinical target, though comprehensive systematic in vivo pharmacodynamic and translational animal validation remains absent in the current study and requires further independent investigation.
Simple Summary PIK3CA is one of the most frequently altered cancer-related genes and has become an important focus of precision oncology. However, the biological and clinical implications of PIK3CA alterations vary considerably across tumor types, and translating this knowledge into effective treatments remains challenging. This review provides a comprehensive, updated, and comparative overview of PIK3CA biology, its molecular alterations across human cancers, their prognostic and therapeutic relevance, and the current development of treatments targeting the pathway activated by PIK3CA. We critically examine both established evidence and remaining limitations, including treatment toxicity and resistance, and discuss emerging therapeutic and molecular approaches. By bringing these different aspects together, we aim to provide oncologists and researchers with a practical framework for understanding the current state of the field, interpreting available evidence, identifying unresolved questions, and designing future clinical and translational studies.
A. Ottaiano, Carmine Picone, M. Santorsola et al.· Cancers· 0 citations
Bladder cancer (BLCA) is a common and heterogeneous malignancy in which disease progression is driven not only by tumor-intrinsic alterations but also by dynamic interactions within the tumor microenvironment (TME). Increasing evidence positions the extracellular matrix (ECM) as a critical regulator of these processes. Matricellular proteins (MCPs), a group of nonstructural ECM-associated molecules, have emerged as key modulators of tumor–stroma communication. In BLCA, MCPs have been reported to display divergent, and in some cases opposing, associations or functions, with the same protein participating in both tumor promotion and suppression. Here, we review current evidence on the function of MCPs in BLCA and synthesize their bidirectional roles in carcinogenesis. MCPs contribute to tumor progression by promoting invasion, epithelial–mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. At the same time, MCPs can restrain tumor growth by inhibiting angiogenesis, stabilizing ECM organization, inducing cell cycle arrest, and maintaining epithelial integrity. A key concept emerging from this body of evidence is the context-dependent functional plasticity of MCPs. We propose that MCP-associated phenotypes in BLCA may be influenced by contextual factors, including isoform diversity arising from alternative splicing and post-translational modifications, spatial compartmentalization within tumor and stromal niches, tumor microenvironmental composition, and molecular subtype. However, the level of supporting evidence differs substantially among MCPs, and direct BLCA-specific mechanistic evidence remains limited for many proposed relationships. These factors, therefore, provide a framework for interpreting divergent findings rather than representing universally established determinants of MCP function. Recognizing MCPs as context-sensitive regulators rather than fixed tumor-promoting or tumor-suppressing entities provides a unifying framework for understanding their roles in BLCA. This could be an important step for therapeutic targeting, encouraging effective strategies to consider and incorporate the molecular and microenvironmental context in which MCPs operate.
Azamat Akhmetkaliyev, José Héctor Gibrán Fritz García, E. Sonnenberg-Riethmacher et al.· International Journal of Mol...· 0 citations
Breast cancer (BC) development is influenced by multifactorial mechanisms. Despite significant advancements in early diagnostic techniques and comprehensive therapeutic approaches, BC continues to pose a substantial threat to women's health, exhibiting persistently high incidence and mortality rates. The Notch signaling pathway, a highly conserved evolutionary pathway initially identified in Drosophila, has garnered extensive research interest and is implicated in the pathogenesis of diverse malignancies, including BC. However, accumulating evidence reveals a highly context-dependent role for Notch signaling in cancer, with documented functions ranging from oncogenic to tumor-suppressive depending on the specific cellular and microenvironmental context. Current evidence indicates that Notch1-4 display nonredundant functional divergence in BC. In this review, we discuss how receptor-specific regulatory mechanisms shape distinct Notch1-4 signaling outputs and summarize the context-dependent functions and molecular mechanisms of Notch receptors across tumor-cell states, BC molecular subtypes, and tumor microenvironmental components. We also review current advances and limitations in pan-Notch inhibition and receptor-specific targeting strategies, aiming to provide clearer directions for future Notch receptor-targeted therapy in BC.
Mei Wang, Yue Mi, Qinong Ye· Cell communication and signa...· 0 citations
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