Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

6-acetoxy-anopterine: A novel structure class of mitotic inhibitor disrupting microtubule dynamics in prostate cancer cells

ABSTRACT: The lack of a cure for metastatic prostate cancer (PCa) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the molecular mechanism of action of the natural product 6-acetoxy-anopterine (6-AA) in malignant cells of the prostate. This potent cytotoxic alkaloid from the endemic Australian tree Anopterus macleayanus induced at low nanomolar doses a strong accumulation of LNCaP and PC3 PCa cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared to vinblastine, highlighting pathways involved in mitosis, microtubule spindle organisation and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced microtubule polymer mass in vitro. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids or 2-methoxyestradiol did not confer cross-resistance to 6-AA, suggesting a different mechanism of microtubule interaction. Finally, 6-AA is the first-in-class microtubule inhibitor that features the unique anopterine scaffold. Altogether, this study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81277 | GEO | 2016/05/11

SECONDARY ACCESSION(S): PRJNA321170

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

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.

2016-06-17 | GSE83459 | GEO

Transcription Level Response of HEK-293T Cells to RfA1 Expression

Project description:We transfected HEK-293T cells to express RfA1. The RNA-Seq results indicates that Genes evolved in biological processes such as “regulation of microtubule cytoskeleton organization”, “microtubule polymerization or depolymerization”, “microtubule nucleation” were found to respond to RfA1 expression. Correspondingly, these microtubule relevant genes were also sorted to cellular component items, including “spindle microtubule”, “spindle pole centrosome”, “mitotic spindle”, “spindle” , which indicates the tight relationship between RfA1 and microtubules.

2021-11-01 | GSE186861 | GEO

Knockout of Staufen1 impairs the localization of specific subsets of mRNAs on the mitotic spindle of colorectal cancer cells

Project description:Staufen1 (STAU1) is an RNA-binding protein involved in maturation, localization, translation and decay of mRNAs. STAU1 expression is modulated during the cell cycle and decreases during mitosis. In prometaphase, STAU155 binds specific classes of mRNAs that code for proteins implicated in transcription and cell cycle regulation. In this paper, we report that STAU155 co-localizes with microtubules on the mitotic spindle in human colorectal cancer cell line HCT116, and map the molecular determinant required for this association within the N-terminal 88 amino acids (aa 25-37). Interestingly, STAU1 co-purifies with ribosomal proteins and co-localizes with active sites of translation on the mitotic spindle. To characterize STAU1-dependent mRNA transport and localization on the spindle, we used RNAseq analysis to identify spindle-associated mRNAs on purified spindles of wild-type and STAU1-KO CRISPR cell lines. Our datasets identify 161 protein-coding transcripts that are less abundant on the mitotic spindle of STAU1-KO cells compared to WT, and 660 that are more abundant. Altogether, these data demonstrate that STAU1 controls the transport and the localization of specific sub-populations of mRNAs to the mitotic spindle of cancer cells and suggest that at least some spindle-localized mRNAs undergo local translation during mitosis.

2019-10-05 | GSE138441 | GEO

MicroRNA expression profiling of the prostate biopsy samples from African American and European American prostate cancer patients

Project description:Prostate cancer (PCa) tends to be more aggressive and lethal in African Americans (AA) compared to European Americans (EA). To further understand the thebiological risk factors associated with PCa disparities observed in AA and EA patients, we performed microRNA profiling using Agilent Human miRNA arrays to identify the differentially expressed microRNAs beween: 1) AA and EA PCa patients; 2) AA PCa vs. AA normal; and 3) EA PCa vs. EA normal. 54 prostate biopsy specimens (tumor and adjacent normal tissues) were collected from 14 African American and 13 European American prostate cancer patients. 54 RNA samples, purified from the collected biopy specimens using Qiagen miRNeasy kit, were process and applied to Agilent human miRNA arrays. Array data was normalized and analyzed using Agilent GeneSpring program.

2015-07-27 | E-GEOD-64318 | biostudies-arrayexpress

Chemical cross-linking of the Spindly-RZZ complex followed by mass spectrometry

Project description:Kinetochores are macromolecular assemblies that connect chromosomes to spindle microtubules during mitosis. The metazoan-specific ≈800 kilodalton ROD-Zwilch-ZW10 (RZZ) complex builds a fibrous corona that assembles on mitotic kinetochores prior to microtubule attachment to promote chromosome alignment and robust spindle assembly checkpoint signaling. Here, we combine biochemical reconstitutions, single particle electron cryo microscopy, cross-linking mass spectrometry, and structural modeling to build a complete model of human RZZ

2022-02-28 | PXD005287 | Pride

MicroRNA expression profiling of the prostate biopsy samples from African American and European American prostate cancer patients

2015-07-27 | GSE64318 | GEO

Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression during mitosis

Project description:Canonical Wnt signaling plays critical roles in development and tissue renewal by regulating β-catenin target genes. Recent evidence showed that β-catenin-independent Wnt signaling is also required for faithful execution of mitosis. This mitotic Wnt signaling functions through Wnt-dependent stabilization of proteins (Wnt/STOP), as well as through components of the LRP6 signalosome. However, the targets and specific functions of mitotic Wnt signaling still remain uncharacterized. Using phosphoproteomics, we identified that Wnt signaling regulates the microtubule depolymerase KIF2A during mitosis. We found that Dishevelled recruits KIF2A via its N-terminal and motor domains, which is further promoted upon LRP6 signalosome formation during mitosis. We show that Wnt signaling modulates KIF2A interaction with PLK1, which is critical for KIF2A localization and the assembly of a bipolar mitotic spindle. Accordingly, Wnt signaling promotes chromosome congression during metaphase by monitoring KIF2A protein levels at the spindle poles both in somatic cells and in pluripotent stem cells. Our findings highlight a novel function of Wnt signaling during cell division, which could have important implications for genome maintenance, notably in stem cells.

2021-11-17 | PXD022724 | Pride

Copy number profiling of prostate cancers from 40 African American patients

Project description:African American (AA) men have a significantly higher mortality rate from prostate cancer (PCa) compared to European American (EA) men. AA men are twice as likely to die from PCa compared to EA men and 8 times as likely as Asian American men to die from PCa. The biological basis for these differences in PCa mortality are unclear. We carried out Copy Number Alteration (CNA) studies on a new set of 40 highly tumor-enriched primary PCas and matched benign prostate tissues from AA men using high resolution Affymetrix 6.0 SNP arrays and expression array analysis using RNAs (GSE71016) from the same tissues using high purity tumors from AA men and matched benign tissue. We have confirmed the specific loss of 4p16.3 described previously and identified a novel tumor suppressor gene, RGS12 at this locus that shows significantly decreased expression in AA PCa but not EA EA PCa.

2018-06-06 | GSE95726 | GEO

Gene expression profiling of the prostate biopsy samples from African American and European American prostate cancer patients

2015-07-27 | GSE64331 | GEO

Gene expression profiling of African-American prostate cancer

Project description:African-American (AA) men have both a higher incidence and significantly higher mortality rates from prostate cancer (PCa) than European American (EA) men. In this study we have carried out a detailed analysis of both CNAs and gene expression changes in PCas from AA men compared to their matched benign tissues. We have identified MNX1 as a novel androgen regulated oncogene that is upregulated to a greater degree in AA PCa compared to EA PCa. Furthermore, RGS12 is a novel tumor suppressor on 4p16.3 that is preferentially deleted in AA PCa which negatively regulates MNX1 expression.

2016-08-31 | GSE71016 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data