VMY-1-103 is a novel CDK inhibitor that disrupts chromosome organization and delays metaphase progression in medulloblastoma cells

Ringer, Lymor; Sirajuddin, Paul; Heckler, Mary M.; Ghosh, Anup; Suprynowicz, Frank A.; Yenugonda, Venkata Mahidhar; Brown, Milton L.; Toretsky, Jeffrey A.; Üren, Aykut; Lee, Yi-Chien; MacDonald, Tobey J.; Rodriguez, Olga; Glazer, Robert I.; Schlegel, Richard; Albanese, Chris

doi:10.4161/cbt.12.9.17682

Cited by 18 publications

(30 citation statements)

References 34 publications

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“…DAOY cells resemble the Shh subgroup of MB [38], and SOX2 expression tends to be higher in this subgroup relative to other MB subgroups [39], [40]. However, as a group, SOX2-associated proteins identified in our study are not enriched in any particular subgroup.…”

Section: Discussioncontrasting

confidence: 49%

The SOX2-Interactome in Brain Cancer Cells Identifies the Requirement of MSI2 and USP9X for the Growth of Brain Tumor Cells

et al. 2013

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Medulloblastomas and glioblastomas, the most common primary brain tumors in children and adults, respectively, are extremely difficult to treat. Efforts to identify novel proteins essential for the growth of these tumors may help to further our understanding of the biology of these tumors, as well as, identify targets for future therapies. The recent identification of multiple transcription factor-centric protein interaction landscapes in embryonic stem cells has identified numerous understudied proteins that are essential for the self-renewal of these stem cells. To identify novel proteins essential for the fate of brain tumor cells, we examined the protein interaction network of the transcription factor, SOX2, in medulloblastoma cells. For this purpose, Multidimensional Protein Identification Technology (MudPIT) identified >280 SOX2-associated proteins in the medulloblastoma cell line DAOY. To begin to understand the roles of SOX2-associated proteins in brain cancer, we focused on two SOX2-associated proteins, Musashi 2 (MSI2) and Ubiquitin Specific Protease 9x (USP9X). Recent studies have implicated MSI2, a putative RNA binding protein, and USP9X, a deubiquitinating enzyme, in several cancers, but not brain tumors. We demonstrate that knockdown of MSI2 significantly reduces the growth of DAOY cells as well as U87 and U118 glioblastoma cells. We also demonstrate that the knockdown of USP9X in DAOY, U87 and U118 brain tumor cells strongly reduces their growth. Together, our studies identify a large set of SOX2-associated proteins in DAOY medulloblastoma cells and identify two proteins, MSI2 and USP9X, that warrant further investigation to determine whether they are potential therapeutic targets for brain cancer.

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Section: Discussioncontrasting

confidence: 49%

The SOX2-Interactome in Brain Cancer Cells Identifies the Requirement of MSI2 and USP9X for the Growth of Brain Tumor Cells

et al. 2013

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“…The prostate cells were fixed and stained with 20ug/ml propidium iodide (PI) and 5 U RNase A, and the DNA content and SubG1 DNA fragmentation was measured using a FACStar Plus system (Becton-Dickson, Franklin Lakes, NJ) as previously described [ 26 , 27 ]. Cellular apoptosis was also assessed by APC-Annexin V antibody (Biolegend, San Diego, CA) staining immediately after treatment with VMY and analyzed using FACStar Plus dual laser FACSort system (Becton-Dickson, Franklin Lakes, NJ) as previously described by us [ 26 , 27 , 49 , 50 ].…”

Section: Methodsmentioning

confidence: 99%

“…Protein extracts were separated on 4-20% Tris-glycine gels and electro-blotted onto PVDF membranes as previously described [ 13 , 26 , 27 ]. Protein levels were assessed using antibodies against p53 (Millipore, #05-224), PARP (Cell Signaling, Danvers, MA #9542), b-actin (Cell Signaling, Danvers, MA #4967), p21 (Santa Cruz #SC 756), LC3B (Cell Signaling, Danvers, MA #3868S) and P62 (Cell Signaling, Danvers, MA #5114S) Densitometry was performed using ImageJ analysis software (NIH, Bethesda, MD) as previously described [ 13 , 26 , 27 ].…”

Section: Methodsmentioning

confidence: 99%

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The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells

et al. 2014

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The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer.

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“…Previous studies indicated that CDK1 plays an important role in neuroblastoma, an embryonal tumor, (Ringer et al, 2011). In addition, another study shown siRNA, MK-1775, could mediate knockdown of WEE1, a kinase known to participate in the G2/M cell cycle and checkpoint and DNA replication during S phase, to reduce medulloblastoma cell proliferation (Hirai et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of Key Genes and Pathways for Medulloblastoma as a Therapeutic Target

Aghamaleki

Mollashahi

Aghamohammadi

et al. 2019

Asian Pac J Cancer Prev

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Introduction:One of the major challenges in cancer treatment is the lack of specific and accurate treatment in cancer. Data analysis can help to understand the underlying molecular mechanism that leads to better treatment. Increasing availability and reliability of DNA microarray data leads to increase the use of these data in a variety of cancers. This study aimed at applying and evaluating microarray data analyzing, identification of important pathways and gene network for medulloblastoma patients to improve treatment approaches especially target therapy. Methods:In the current study, Microarray gene expression data (GSE50161) were extracted from Geo datasets and then analyzed by the affylmGUI package to predict and investigate upregulated and downregulated genes in medulloblastoma. Then, the important pathways were determined by using software and gene enrichment analyses. Pathways visualization and network analyses were performed by Cytoscape. Results: A total number of 249 differentially expressed genes (DEGs) were identified in medulloblastoma compared to normal samples. Cell cycle, p53, and FoxO signaling pathways were indicated in medulloblastoma, and CDK1, CCNB1, CDK2, and WEE1 were identified as some of the important genes in the medulloblastoma. Conclusion: Identification of critical and specific pathway in any disease, in our case medulloblastoma, can lead us to better clinical management and accurate treatment and target therapy.

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VMY-1-103 is a novel CDK inhibitor that disrupts chromosome organization and delays metaphase progression in medulloblastoma cells

Cited by 18 publications

References 34 publications

The SOX2-Interactome in Brain Cancer Cells Identifies the Requirement of MSI2 and USP9X for the Growth of Brain Tumor Cells

The SOX2-Interactome in Brain Cancer Cells Identifies the Requirement of MSI2 and USP9X for the Growth of Brain Tumor Cells

The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells

Bioinformatics Analysis of Key Genes and Pathways for Medulloblastoma as a Therapeutic Target

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