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Selective Cancer Cell Targeting through the Development of a Novel Pan-Cancer Myc Modulator that Induces Mitotic Catastrophe

ABSTRACT: Selective Cancer Cell Targeting through the Development of a Novel Pan-Cancer Myc Modulator that Induces Mitotic Catastrophe

PROVIDER: PRJNA1110243 | ENA |

REPOSITORIES: ENA

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Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe

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

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Pan-cancer Myc modulator that targets Myc-α-tubulin interaction to drive selective mitotic catastrophe.

Project description: Not available

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Dysregulation of microtubule dynamics caused by LOXL3 knockout triggers mitosis catastrophe and senescence in U87MG and U251 cells

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.

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MYDGF Deficiency Exacerbates Mitotic Catastrophe of Podocytes in Glomerular Disease

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FBX-DMEP suppresses hepatocellular carcinoma through tubulin-associated mitotic dysregulation

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Thalicthuberine: A Novel Mitotic Inhibitor in Prostate Cancer Cells

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.

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Mitotic MAX bookmarking drives MYC-dependent hyper-transcription at TBP-bound promoters

Project description:Shortly after cell division, a robust wave of hyper-transcription reactivates the genome1-3. This phenomenon is particularly pronounced in pluripotent cells4, which necessitate rapid transcriptome reactivation to maintain their undifferentiated state and prevent premature differentiation. While recent work has illuminated how specific groups of genes are reactivated4-8, the mechanisms enabling the global, efficient and accurate post-mitotic reactivation of the genome remain unknown. Here we elucidate the direct involvement of the MYC/MAX transcription factors in the post-mitotic reactivation of pluripotent mouse embryonic stem cells. While MYC undergoes extensive phosphorylation and largely dissociates from its DNA binding sites during mitosis, we report that MAX remains bound to its targets, preferentially at promoters, and facilitates early recruitment of MYC following mitosis. Through the application of MYC/MAX heterodimerization inhibitors, we demonstrate their indispensable role in sustaining hyper-transcription in ES cells, including during the critical transition from mitosis to G1 phase. Our findings uncover a novel role for MAX in mitotic bookmarking, highlighting its pivotal role in post-mitotic MYC recruitment and the re-establishment of high global transcription levels. These findings hold significant implications for medically relevant contexts, particularly when cell proliferation is of paramount importance. We anticipate that the study of mitotic bookmarking by MYC and MAX and of the effects of anti-cancer drugs targeting MYC/MAX interactions in such process will be relevant for our understanding of cancer and its potential treatments.

2026-07-09 | PXD063728 | Pride

Nakiterpiosin targets tubulin and triggers mitotic catastrophe in human cancer cells.

Project description: Not available

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PIAS2b dsRNAi repression kills by mitotic catastrophe anaplastic thyroid and non-thyroid carcinomas, but not normal thyroid or differentiated carcinomas

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

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