Selective Cancer Cell Targeting through the Development of a Novel Pan-Cancer Myc Modulator that Induces Mitotic Catastrophe
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ABSTRACT:
PROVIDER: PRJNA1110243 | ENA |
REPOSITORIES: ENA
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Project description:MYC overexpression is a well-established cancer vulnerability, yet direct therapeutic targeting of Myc remains a challenge. Here, we identify DL78 as a potent antimitotic agent with selective anticancer activity through its regulation of Myc. DL78 demonstrated broad efficacy by inhibiting growth across nine cancer types and significantly reducing tumor burden in an in vivo model of platinum-resistant high-grade serous ovarian cancer, with no overt toxicity. DL78 preferentially targets chromosomally unstable, MYC-overexpressing cancer cells, a hallmark of high-grade serous ovarian cancer. Mechanistically, DL78 exploits Myc’s role in mitotic entry by disrupting its interaction with α-tubulin, leading to sustained mitotic arrest, mitotic catastrophe, and apoptosis while sparing nonmalignant cells. This study establishes a novel paradigm for Myc-targeted therapy by introducing DL78, which induces cancer-selective mitotic catastrophe by disrupting Myc’s interaction with α-tubulin rather than its transcriptional activity
2025-09-08 | GSE267208 | GEO
Project description:The amine oxidase LOXL3 has been implicated in tumor development and progression, with elevated expression in glioblastoma (GBM). This enzyme influences GBM cell adhesion, migration, and proliferation, and is demonstrated correlation with tubulin expression. Microtubules, as the major component of the cytoskeleton, are crucial for cell cycle and mitotic progression. In this study, LOXL3 knockout was performed using CRISPR-Cas9 in two GBM cell lines, U87MG and U251, to achieve high silencing efficiency. The knockdown resulted in decreased cell viability in both cell lines. Transcriptome enrichment analysis of U87MG cells revealed downregulation of genes associated to tubulin acetylation, which was subsequently confirmed by Western blot analysis. Both U87MG and U251 cells exhibited downregulation of cell cycle and proliferation-related genes. Functional assays confirmed that LOXL3-knockout cells exhibited delayed cell cycle progression and significant alterations in mitotic spindles during metaphase-anaphase transition. Nuclear analysis revealed morphological changes indicative of mitotic catastrophe in U87MG cells and senescence in U251 cells. Additionally, LOXL3-knockout clones displayed reduced cell adhesion and migration. Interestingly, LOXL3 knockdown in GBM cell lines reduces tubulin acetylation, leading to mitotic catastrophe and subsequent cell death in a TP53 mutation-dependent manner. These findings highlight the potential of targeting LOXL3 as a combinatory strategy for advancing research and developing novel therapeutic approaches in TP53-mutated GBM.
2026-01-22 | GSE288138 | GEO
Project description:MYDGF Deficiency Exacerbates Mitotic Catastrophe of Podocytes in Glomerular Disease
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Project description:Bioassay-guided fractionation of a cytotoxic extract derived from the Australian endemic plant Hernandia albiflora (twigs) resulted in the isolation of the two known compounds: deoxypodophyllotoxin and thalicthuberine. Both compounds were tested for their inhibition of LNCaP cell viability. Thalicthuberine (TH, IC50=2.0 µM) was selected for mechanism of action studies. Ongoing investigations have shown that TH induced a strong accumulation of LNCaP cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. However, unlike microtubule-targeting drugs (vinblastine, paclitaxel and nocodazole), TH did not affect tubulin polymerization in a cell-free system, while it reduced cellular microtubule polymer mass, suggesting that TH indirectly targets microtubule dynamics through inhibition of critical regulators or tubulin-associated proteins. Based on phenotypic comparisons, we excluded the mitotic regulators Aurora kinase A and Polo-like kinase 1 as potential targets of TH. TH did not directly interact with DNA (cell-free assay) or induce DNA damage in cells. Further experiments will attempt to address the molecular target(s) and inhibition mechanism of TH. This is the first report of a mechanism of action study for this natural product. Based on these results, TH has great promise for further development into a potent non-tubulin-targeting mitotic inhibitor.
2016-06-17 | GSE83459 | GEO
Project description:Targeting EYA2 tyrosine phosphatase activity in glioblastoma stem cells induces mitotic catastrophe
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Project description:The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with very high mortality. Double-stranded RNA–directed RNA interference (dsRNAi) targeting the PIAS2 isoform beta (PIAS2b) inhibits growth of ATC cell lines and patient primary cultures in vitro and orthotopic patient-derived xenografts (oPDX) in vivo, but not of thyroid cell lines or non-anaplastic primary thyroid cultures (differentiated carcinoma, benign lesions, or normal). PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. Strikingly, PIAS2b-dsRNAi induces mitotic catastrophe at prophase. High-throughput proteomics revealed the proteasome (PSMC5) and spindle cytoskeleton as direct targets of PIAS2b SUMOylation at mitotic initiation. PIAS2b-dsRNAi is a promising therapy for ATC and other aggressive anaplastic cancers.
2024-04-08 | PXD044110 | Pride
Project description:Background: During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5—a critical MYC cofactor—regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein. Results: Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus. Conclusions: Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes.
2024-03-29 | GSE244835 | GEO
Project description:Background: During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5—a critical MYC cofactor—regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein. Results: Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus. Conclusions: Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes.
2024-03-29 | GSE244899 | GEO
Project description:Agents that interfere with mitotic progression by perturbing microtubule dynamics are commonly used for cancer chemotherapy. Here, we identify nakiterpiosin as a novel antimitotic drug that targets microtubules. Nakiterpiosin induces mitotic arrest and triggers mitotic catastrophe in human cancer cells by impairing bipolar spindle assembly. At higher concentration, it alters the interphase microtubule network and suppresses microtubule dynamics. In the presence of nakiterpiosin, microtubules are no longer arranged in a centrosomal array and centrosome-mediated microtubule regrowth after cold depolymerization is inhibited. However, centrosome organization, the ultrastructure of Golgi stacks, and protein secretion are not affected, suggesting that the drug has minimal toxicity toward other cellular functions. Nakiterpiosin interacts directly with tubulin, inhibits microtubule polymerization in vitro, and decreases polymer mass in cells. Furthermore, it enhances tubulin acetylation and reduces viability of paclitaxel-resistant cancer cells. In conclusion, nakiterpiosin exerts antiproliferative activity by perturbing microtubule dynamics during mitosis that activates the spindle assembly checkpoint and triggers cell death. These findings suggest the potential use of nakiterpiosin as a chemotherapeutic agent.
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Project description:Elongator is a tRNA-modifying complex regulating protein translation. Recently, a moonlighting function of Elongator has been identified in regulating the polarization of the microtubule cytoskeleton during asymmetric cell division. Elongator induces symmetry breaking of the anaphase midzone by selectively stabilizing microtubules on one side of the spindle, contributing to the downstream polarized segregation of cell-fate determinants and therefore to cell fate determination. Here, we show how Elongator controls microtubule dynamics. Elongator binds simultaneously to the tip of microtubules and also to free GTP-tubulin heterodimers using two different subcomplexes, Elp123 and Elp456, respectively. We show that these activities must be coupled for Elongator to decrease the critical concentration of tubulin for microtubule elongation. As a consequence, Elongator increases microtubule growth speed and decreases their catastrophe rate. Surprisingly, we found that Elp456 binds to tubulin tails and has strong selectivity towards polyglutamylated tubulin. Hence, microtubules assembled by Elongator become selectively enriched with polyglutamylated tubulin. Therefore, Elongator rewrites the tubulin code of growing microtubules, placing it at the core of cytoskeletal dynamics and polarization during asymmetric cell division.
2025-05-07 | PXD058480 | Pride