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11 recordsLinked to original sources
PubMed2026

Kinesins in Cancer Drug Resistance: Mechanisms, Therapeutic Targeting, and Translational Potential.

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.

biomarker potential↗
PubMed2023

Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling.

BACKGROUND: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown. METHODS: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy. RESULTS: C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells. CONCLUSION: We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.

Animals↗
PubMed2026

A guide to selecting high-performing renewable antibodies for KIF5A (Q12840) across western blot, immunoprecipitation, and immunofluorescence.

Kinesin Family Member 5A (KIF5A) is an important protein for anterograde cellular transport. We characterized ten commercially available research antibodies against KIF5A for use in western blot, immunoprecipitation, and immunofluorescence using a standardized workflow. Antibody performance was assessed by comparing signal in a wild-type cell line and its corresponding knockout derivative. This work is part of a broader collaborative public-good initiative to improve biomedical research by systematically evaluating commercial antibodies against human proteins and openly sharing the data as a resource for the scientific community. We encourage readers to use this report as a guide for selecting antibodies best suited to their specific applications.

Kinesins↗
PubMed2026

Natural Product Target Identification of Wheldone, a Fungal Metabolite, as a KIF11 Inhibitor in Ovarian Cancer Using the DiffPOP (Differential Protein Precipitation) Method.

Wheldone, a fungal metabolite, was identified as a cytotoxic compound in high-grade serous ovarian cancer (HGSOC). Wheldone induced caspase 3/7-dependent apoptosis and reduced migration, invasion, and spheroid growth. Wheldone stimulated apoptosis in chemoresistant HGSOC models. Wheldone treatment caused significant downregulation of HNRNPD, a DNA repair protein, and increased DNA damage that could be blocked by N-acetyl-L-cysteine. In vivo, wheldone displayed minimal toxicity but was rapidly cleared from circulation, despite in vitro metabolic stability. Wheldone treatment in vivo did not demonstrate significant reduction in tumor burden. Therefore, in order to overcome these liabilities, it was necessary to find the protein target of wheldone so that modifications can be made to improve the drug-like characteristics of the compound. Using the drug-target interaction proteomics method, differential precipitation of proteins, wheldone was found to act as an inhibitor of Kinesin superfamily protein 11 (KIF11), a motor protein essential for mitotic spindle formation. An ATPase biochemical cell-free assay confirmed direct binding and functional inhibition of KIF11. Wheldone resulted in G2/M arrest and downstream regulation of mitotic proteins such as TPX2, AURKA, and phospho-histone H3. Proteomics after treatment of wheldone in four different HGSOC cancer cell lines all supported changes consistent with mitotic spindle assembly disruption. Further, KIF11 was one of only 13 proteins upregulated in all 4 cell lines treated. Overall, wheldone was found to be a fungal metabolite that inhibits KIF11 in chemoresistant ovarian cancer, with future studies needed to improve its pharmacokinetics and delivery.

Female↗
PubMed2025

Alternative spliceosomal protein Eftud2 mediated Kif3a exon skipping promotes SHH-subgroup medulloblastoma progression.

Alternative splicing plays a pivotal role in various facets of organogenesis, immune response, and tumorigenesis. Medulloblastoma represents a prevalent childhood brain tumor, with approximately one-third classified as the Sonic Hedgehog (SHH) subgroup. Nevertheless, the contribution of alternative splicing to medulloblastoma oncogenesis remains elusive. This investigation delineated an upregulation of the spliceosomal protein Eftud2 in the SHH-subgroup medulloblastoma mouse model and human medulloblastoma patients. Targeted ablation of Eftud2 in granule precursor cells (GNPs) within the cerebellum prolonged the survival of SHH-subgroup medulloblastoma mice, indicating a putative association between Eftud2 expression and medulloblastoma prognosis. Functional assays unveiled that EFTUD2 depletion in human medulloblastoma cells significantly curtailed cellular proliferation by impeding the activation of the SHH signaling pathway. Through multi-omics sequencing analysis, it was discerned that Eftud2 influences exons 10-11 skipping of Kif3a, a kinesin motor critical for primary cilia formation. Notably, exons 10-11 skipping in Kif3a augmented human medulloblastoma cell proliferation by potentiating the transcriptional activity of Gli2. These findings underscore a robust correlation between Eftud2 and SHH-subgroup medulloblastoma, emphasizing its regulatory role in modulating downstream transcription factors through the alternative splicing of pivotal genes within the SHH signaling pathway, thereby propelling the aggressive proliferation of SHH-subgroup medulloblastoma.

Medulloblastoma↗
PubMed2026

Natural variation in GmSOP5 regulates seed oil and protein content during soybean domestication.

Seed oil content, protein content, and yield are agronomically important, correlated traits that determine the economic value of soybean (Glycine max). However, improving seed quality and yield simultaneously is challenging because gains in one breeding target often compromise the other, and the genetic basis of this trade-off is poorly understood. Here, we performed a genome-wide association study of 429 diverse soybean accessions and identified Seed Oil and Protein 5 (SOP5), which encodes a kinesin protein, as a key locus associated with seed oil and protein content. Knockout and overexpression experiments demonstrated that GmSOP5 positively affects seed oil content and 100-seed weight and negatively influences seed protein content. GmSOP5 is located in a selective sweep region, and the domestication-related GmSOP5H1 allele is nearly fixed in cultivated soybean, contributing to increased seed size, weight, and oil content and reduced protein content. Field trials demonstrated that neither loss-of-function GmSOP5-edited mutants, which have increased seed protein content, nor GmSOP5-overexpression lines, which have increased seed oil content, differed significantly in yield from wild-type plants, because changes in plant architecture were offset by changes in seed weight. Our results shed light on soybean domestication and suggest how pleiotropy can be harnessed in breeding to enhance seed quality without compromising yield.

GWAS↗
PubMed2025

Insights into KIF11 pathogenesis in microcephaly-lymphedema-chorioretinopathy syndrome from a lymphatic perspective.

Pathogenic variants in kinesin KIF11 underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association of KIF11 (encoding EG5) with development of the lymphatic system and how KIF11 pathogenic variants lead to lymphatic dysfunction and lymphedema remain unknown. Using patient-derived lymphoblastoid cells, we demonstrated that patients with MLC carrying pathogenic stop-gain variants in KIF11 have reduced mRNA and protein levels. Lymphoscintigraphy showed reduced tracer absorption, and intestinal lymphangiectasia was detected in one patient, pointing to impairment of lymphatic function caused by KIF11 haploinsufficiency. We revealed that KIF11 is expressed in early human and mouse development with the lymphatic markers VEGFR3, podoplanin, and PROX1. In zebrafish, single-cell RNA-Seq identified kif11 specifically expressed in endothelial precursors. In human lymphatic endothelial cells, EG5 inhibition with ispinesib reduced VEGFC-driven AKT phosphorylation, migration, and spheroid sprouting. KIF11 knockdown reduced PROX1 and VEGFR3 expression, providing for the first time to our knowledge a link between KIF11 and drivers of lymphangiogenesis and lymphatic identity.

Humans↗
PubMed2025

Identification and validation of the important role of KIF11 in the development and progression of endometrial cancer.

BACKGROUND: Human kinesin family member 11 (KIF11) plays a vital role in regulating the cell cycle and is implicated in the tumorigenesis and progression of various cancers, but its role in endometrial cancer (EC) is still unclear. Our current research explored the prognostic value, biological function and targeting strategy of KIF11 in EC through approaches including bioinformatics, machine learning and experimental studies. METHODS: The GSE17025 dataset from the GEO database was analyzed via the limma package to identify differentially expressed genes (DEGs) in EC. Functional enrichment analysis of the DEGs was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. DEGs were further screened for hub genes through protein-protein interaction (PPI) network analysis and machine learning. The role of the hub gene KIF11 in EC was analyzed using clinical data from the TCGA database. The expression of KIF11 in EC was subsequently validated in clinical samples. In vitro experiments were utilized to evaluate the effects of KIF11 on biological functions such as proliferation, migration, apoptosis, and the cell cycle in endometrial cancer cells. RESULTS: A total of 877 DEGs, which are widely involved in important biological processes such as cell division, tubulin binding, and the cell cycle, were identified. Through PPI network analysis and machine learning, KIF11 was selected as the hub gene for subsequent analysis and experimental validation. An analysis of TCGA data revealed that KIF11 is highly expressed in EC and is associated with tumor grade, stage, and a low survival rate. The overexpression of KIF11 in tumor tissues was further confirmed in EC patient samples. KIF11 knockdown had inhibitory effects on cell proliferation, migration and invasion. Flow cytometry analysis revealed that KIF11 knockdown induced G2/M phase arrest and promoted apoptosis in EC cells. CONCLUSION: Our study demonstrated that KIF11 was upregulated in EC and was strongly associated with a poor prognosis. Notably, we found that reduced KIF11 expression inhibited EC cell proliferation, migration and invasion. KIF11 knockdown caused more EC cells to arrest in the G2/M phase and undergo apoptosis. The findings of our study emphasized that KIF11 may be a promising prognostic biomarker and therapeutic target for EC patients.

Humans↗
PubMed2025

KIF18A promotes chromosome congression in cooperation with CENP-E downstream of CENP-C.

Chromosome congression is a key process that acts to align chromosomes at the spindle equator via kinetochore-microtubule interactions, with defects in chromosome alignment leading to chromosomal instability. However, defining the mechanisms that underlie chromosome congression is limited due to the multiple factors that act in parallel to regulate chromosome movement. Here, we conducted a genome-wide Cas9-based functional genetics screen using a hypomorphic CENP-C mutant that affects its kinetochore interactions. Our analysis identified KIF18A, whose knockout resulted in synthetic lethality with the CENP-C mutant. Further analysis revealed that the synthetic defect was due to a reduction in CENP-E function in the CENP-C mutant. Our work suggests that KIF18A promotes chromosome alignment in cooperation with CENP-E downstream of CENP-C during early prometaphase. Thus, our analysis enables us to dissect parallel molecular mechanisms for chromosome congression and identify sensitivities and biomarkers that might guide anti-KIF18A chemotherapeutics.

Kinesins↗
PubMed2025

FTO promotes weight gain via altering Kif1a splicing and axonal vesicle trafficking in AgRP neurons.

N6-methyladenosine (m6A) is an abundant chemical RNA modification involved in the regulation of many biological processes. The m6A demethylase FTO (fat mass and obesity-associated protein) is known to affect body weight, but its systemic context and underlying mechanisms remain unclear. Here, we found that mice lacking or overexpressing Fto in agouti-related peptide-expressing (AgRP) neurons in the hypothalamus exhibited decreased and increased body weight, respectively. FTO demethylated m6A on mRNAs for proteins associated with membrane trafficking and alternative splicing in AgRP neurons. Downstream, FTO-modulated alternative splicing of the axonal motor protein Kif1a affected its hinge region, which is relevant to the structure and function of KIF1A. Notably, Kif1a knockdown in AgRP neurons suppressed the weight gain of mice overexpressing Fto. In addition, FTO increased the trafficking and secretion of dense-core vesicles containing neuropeptides NPY and AgRP from AgRP neurons. Collectively, these results reveal a novel regulatory FTO-KIF1A axis in the brain affecting appetite-stimulating AgRP neurons and systemic energy homeostasis, via FTO regulation of the epitranscriptome of AgRP neurons.

Animals↗
PubMed2026

Targeting KIFC1 to disrupt centrosome clustering and trigger anaphase catastrophe in small-cell lung cancer.

Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.

Humans↗