Dicoumarol down-regulates human <i>PTTG1/Securin</i> mRNA expression through inhibition of Hsp90

Hernández, Agustín; López-Lluch, Guillermo; Bernal, Juan A.; Navas, Plácido; Pintor‐Toro, José Antonio

doi:10.1158/1535-7163.mct-07-0457

Cited by 19 publications

(19 citation statements)

References 46 publications

(50 reference statements)

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“…On the other hand, it can mean the induction of further aneuploidy, as a side effect. Recently, we have described that dicoumarol is an unsuspected Hsp90 inhibitor (Hernandez et al, 2008). Also, we showed that treatment of cancer cells with dicoumarol and other Hsp90 inhibitors reduces the levels of securin through repression of its gene.…”

Section: Introductionmentioning

confidence: 95%

“…Floating and adherent cells were stained with propidium iodide and processed for flow cytometry analysis on a Coulter Epics XL apparatus as described (Hernandez et al, 2008). Determination of aneuploidy in cultured cells was estimated according to Muehlbauer and Schuler (2005).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…One microliter of the final cDNA was subjected to PCR as in Hernandez et al (2008). Primers annealing on the glyceraldehyde-3-phosphate dehydrogenase cDNA were used to check equal cDNA loading onto PCR mixes.…”

Section: Semiquantitative Rt-pcrmentioning

confidence: 99%

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HDAC and Hsp90 inhibitors down‐regulate PTTG1/securin but do not induce aneuploidy

Hernández

López-Lluch

Navas

et al. 2008

Genes Chromosomes & Cancer

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Human securin regulates correct chromatid separation. However, there are conflicting reports on the aneugenic effects of its gene deletion. Here we show that PTTG1/securin gene expression is dramatically repressed when Hsp90 or histone deacetylases are inhibited. However, these treatments do not increase the proportion of aneuploid cells. This was also confirmed using RNAi (silencing of PTTG1/securin > or =80%). As expected, histone deacetylases arrested cells in both G1 and G2. However, sec(-/-) HCT116 cells showed a greater disposition to arrest cells in G2 than sec(+/+) cells due to insufficient induction of CDKN1A. These results indicate that chromatid separation is controlled through redundant mechanisms and reveal a new aspect of securin in cell cycle regulation.

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Section: Introductionmentioning

confidence: 95%

Section: Flow Cytometrymentioning

confidence: 99%

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HDAC and Hsp90 inhibitors down‐regulate PTTG1/securin but do not induce aneuploidy

Hernández

López-Lluch

Navas

et al. 2008

Genes Chromosomes & Cancer

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“…Heat shock protein 90 (Hsp90) is an essential molecular chaperone involved in the folding and stabilization of client proteins which regulate the survival of cancer cells. Hsp90 inhibitors have been reported to repress PTTG1 expression in carcinoma cells [10,11], and are thought to act in a similar way in pituitary tumor cells. Previous studies have demonstrated that Hsp90 inhibitors decreased POMC mRNA and ACTH levels in AtT-20 cells [12,13].…”

mentioning

confidence: 99%

Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells

et al. 2015

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“…Earlier studies have used a similar approach using a cell-based system to monitor the Hsp90 protein folding machinery; however, that approach utilized aliquots of cell extracts to examine Hsp90 inhibition, which is not amenable to HTS. 34,35 Furthermore, lysing of the cells to prepare the cell extract has the potential to physically disrupt the Hsp90 heteroprotein complexes, leading to a loss of physiological relevance. In contrast, this approach is novel, as Hsp90 inhibition can be measured in intact cancer cells without disruption of the native complexes.…”

Section: Discussionmentioning

confidence: 99%

Development of a High-Throughput Screening Cancer Cell-Based Luciferase Refolding Assay for Identifying Hsp90 Inhibitors

Sadikot

Swink

Eskew

et al. 2013

ASSAY and Drug Development Technologies

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The 90 kDa heat-shock protein (Hsp90) and other cochaperones allow for proper folding of nascent or misfolded polypeptides. Cancer cells exploit these chaperones by maintaining the stability of mutated and misfolded oncoproteins and allowing them to evade proteosomal degradation. Inhibiting Hsp90 is an attractive strategy for cancer therapy, as the concomitant degradation of multiple oncoproteins may lead to effective anti-neoplastic agents. Unfortunately, early clinical trials have been disappointing with N-terminal Hsp90 inhibitors, as it is unclear whether the problems that plague current Hsp90 inhibitors in clinical trials are related to on-target or off-target activity. One approach to overcome these pitfalls is to identify structurally diverse scaffolds that improve Hsp90 inhibitory activity in the cancer cell milieu. Utilizing a panel of cancer cell lines that express luciferase, we have designed an in-cell Hsp90-dependent luciferase refolding assay. The assay was optimized using previously identified Hsp90 inhibitors and experimental novobiocin analogues against prostate, colon, and lung cancer cell lines. This assay exhibits good interplate precision (% CV), a signal-to-noise ratio (S/N) of ‡7, and an approximate Z-factor ranging from 0.5 to 0.7. Novobiocin analogues that revealed activity in this assay were examined via western blot experiments for client protein degradation, a hallmark of Hsp90 inhibition. Subsequently, a pilot screen was conducted using the Prestwick library, and two compounds, biperiden and ethoxyquin, revealed significant activity. Here, we report the development of an in-cell Hsp90-dependent luciferase refolding assay that is amenable across cancer cell lines for the screening of inhibitors in their specific milieu.

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Dicoumarol down-regulates human PTTG1/Securin mRNA expression through inhibition of Hsp90

Abstract: Securin, the natural inhibitor of sister chromatid untimely separation, is a protooncogene overexpressed in tumors.

Cited by 19 publications

References 46 publications

HDAC and Hsp90 inhibitors down‐regulate PTTG1/securin but do not induce aneuploidy

HDAC and Hsp90 inhibitors down‐regulate PTTG1/securin but do not induce aneuploidy

Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells

Development of a High-Throughput Screening Cancer Cell-Based Luciferase Refolding Assay for Identifying Hsp90 Inhibitors

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