Opposite effects of antimicrotubule agents on c-myc oncogene expression depending on the cell lines used

Bourgarel-Rey, Véronique; Khyari, Saı̈d El; Rimet, Odile; Bordás, Barna; Guigal, Nolwen; Braguer, Diane; Sérée, Eric; Barra, Yves; Briand, Claudette

doi:10.1016/s0959-8049(00)00042-3

Cited by 20 publications

(15 citation statements)

References 25 publications

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“…The mechanism behind this down-regulation is currently unresolved. In contrast we did not observe any down-regulation of MYC levels by microtubule-targeting agents, and the relationship between MYC expression and the cytotoxic effect of these agents appears to be largely context dependent [23], [26]–[28], [46], [47].…”

Section: Discussioncontrasting

confidence: 90%

Identification of Cytotoxic Drugs That Selectively Target Tumor Cells with MYC Overexpression

et al. 2011

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Expression of MYC is deregulated in a wide range of human cancers, and is often associated with aggressive disease and poorly differentiated tumor cells. Identification of compounds with selectivity for cells overexpressing MYC would hence be beneficial for the treatment of these tumors. For this purpose we used cell lines with conditional MYCN or c-MYC expression, to screen a library of 80 conventional cytotoxic compounds for their ability to reduce tumor cell viability and/or growth in a MYC dependent way. We found that 25% of the studied compounds induced apoptosis and/or inhibited proliferation in a MYC-specific manner. The activities of the majority of these were enhanced both by c-MYC or MYCN over-expression. Interestingly, these compounds were acting on distinct cellular targets, including microtubules (paclitaxel, podophyllotoxin, vinblastine) and topoisomerases (10-hydroxycamptothecin, camptothecin, daunorubicin, doxorubicin, etoposide) as well as DNA, RNA and protein synthesis and turnover (anisomycin, aphidicholin, gliotoxin, MG132, methotrexate, mitomycin C). Our data indicate that MYC overexpression sensitizes cells to disruption of specific pathways and that in most cases c-MYC and MYCN overexpression have similar effects on the responses to cytotoxic compounds. Treatment of the cells with topoisomerase I inhibitors led to down-regulation of MYC protein levels, while doxorubicin and the small molecule MYRA-A was found to disrupt MYC-Max interaction. We conclude that the MYC pathway is only targeted by a subset of conventional cytotoxic drugs currently used in the clinic. Elucidating the mechanisms underlying their specificity towards MYC may be of importance for optimizing treatment of tumors with MYC deregulation. Our data also underscores that MYC is an attractive target for novel therapies and that cellular screenings of chemical libraries can be a powerful tool for identifying compounds with a desired biological activity.

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Section: Discussioncontrasting

confidence: 90%

Identification of Cytotoxic Drugs That Selectively Target Tumor Cells with MYC Overexpression

et al. 2011

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“…Moreover, c-myc directly interacts with a-tubulin and microtubules [47,48]. Finally, c-myc expression is affected by drugs which alter microtubule dynamics [48,49]. We found by real-time PCR analysis that c-myc mRNA expression relative to b-actin is about twofold higher in HT29 than in AGS cells (data not shown).…”

Section: Hseg5 Expression In Ags and Ht29 Cellsmentioning

confidence: 82%

Differential effects of monastrol in two human cell lines

Leizerman

Avunie-Masala

Elkabets

et al. 2004

CMLS, Cell. Mol. Life Sci.

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The kinesin-related protein HsEg5 plays essential roles in mitotic spindle dynamics. Although inhibition of HsEg5 has been suggested as an aid in cancer treatment, the effects of such inhibition on human cells have not been characterized. Here we studied the effects of monastrol, an allosteric HsEg5 inhibitor, on AGS and HT29 cell lines and compared them to those of taxol. While both cell lines were similarly sensitive to taxol, AGS cells were more sensitive to monastrol. The differences in sensitivity were determined by the degree of inhibitory effect on cell proliferation, reversibility of monastrol-induced G2/M arrest, intracellular phenotypes and induction of apoptosis. In both cell lines, monastrol-induced apoptosis was accompanied by mitochondrial membrane depolarization and poly-ADP-ribose polymerase 1 cleavage. In AGS, but not HT29 cells, monastrol-induced apoptosis involved a prominent cleavage of procaspases 8 and 3. While in AGS cells, monastrol induced the formation of symmetric microtubule asters only, in HT29 cells, asymmetric asters were also formed, which may be related to specific HsEg5 functions in HT29 cells.

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“…Similarly, pools of NF-B/IB␣ may be associated with actin or actinbinding proteins and following degradation of IB␣, the released RelA/p65 may interact with actin cytoskeleton for its nuclear localization. Given that various agents/drugs modulate RelA/p65 nuclear translocation depending upon the cell type (53)(54)(55)(56)(57)(58), such a possibility cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Actin Cytoskeleton-dependent and -independent Pathways for RelA/p65 Nuclear Translocation in Endothelial Cells

Fazal

Minhajuddin

Bijli

et al. 2007

Journal of Biological Chemistry

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Activation of the transcription factor NF-B involves its release from the inhibitory protein IB␣ in the cytoplasm and subsequently, its translocation to the nucleus. Whereas the events responsible for its release have been elucidated, mechanisms regulating the nuclear transport of NF-B remain elusive. We now provide evidence for actin cytoskeleton-dependent and -independent mechanisms of RelA/p65 nuclear transport using the proinflammatory mediators, thrombin and tumor necrosis factor ␣, respectively. We demonstrate that thrombin alters the actin cytoskeleton in endothelial cells and interfering with these alterations, whether by stabilizing or destabilizing the actin filaments, prevents thrombin-induced NF-B activation and consequently, expression of its target gene, ICAM-1. The blockade of NF-B activation occurs downstream of IB␣ degradation and is associated with impaired RelA/p65 nuclear translocation. Importantly, thrombin induces association of RelA/p65 with actin and this interaction is sensitive to stabilization/destabilization of the actin filaments. In parallel studies, stabilizing or destabilizing the actin filaments fails to inhibit RelA/p65 nuclear accumulation and ICAM-1 expression by tumor necrosis factor ␣, consistent with its inability to induce actin filament formation comparable with thrombin. Thus, these studies reveal the existence of actin cytoskeleton-dependent and -independent pathways that may be engaged in a stimulus-specific manner to facilitate RelA/p65 nuclear import and thereby ICAM-1 expression in endothelial cells. NF-B2 is an ubiquitously expressed family of transcription factors controlling varied biological effects ranging from inflammatory, immune, and stress-induced responses to cell fate decisions such as proliferation, differentiation, tumorigenesis, and apoptosis (1-3). NF-B dimers, typically a heterodimer of p50 and RelA/p65 subunits, are mostly sequestered in the cytoplasm by IB␣, the prototype of a family of inhibitory proteins IBs that mask the nuclear localization signal of RelA/ p65 (4, 5). Activation of NF-B requires serine phosphorylation (Ser 32 and Ser 36 ) of IB␣ by a macromolecular IB kinase (IKK) complex (6 -8). Phosphorylation marks IB␣ for polyubiquitination by the E3-SCF␤-TrCP ubiquitin ligase leading to its degradation by the 26 S proteasome (9 -11). The released NF-B undergoes rapid nuclear translocation and subsequent binding to NF-B responsive elements to activate transcription of target genes including intercellular adhesion molecule-1 (ICAM-1; CD54), an inducible endothelial adhesive protein that serves as a counter-receptor for ␤ 2 -integrins (CD11/CD18) present on the surface of leukocytes (12-14). Interaction of ICAM-1 with ␤ 2 -integrins enables polymorphonuclear leukocytes to adhere firmly and stably to the vascular endothelium, and to migrate across the endothelial barrier (15-18). have shown that activation of NF-B is essential for ICAM-1 expression in endothelial cells after stimulation with the proinflammatory cytokine tumor necrosis factor ...

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Opposite effects of antimicrotubule agents on c-myc oncogene expression depending on the cell lines used

Cited by 20 publications

References 25 publications

Identification of Cytotoxic Drugs That Selectively Target Tumor Cells with MYC Overexpression

Identification of Cytotoxic Drugs That Selectively Target Tumor Cells with MYC Overexpression

Differential effects of monastrol in two human cell lines

Evidence for Actin Cytoskeleton-dependent and -independent Pathways for RelA/p65 Nuclear Translocation in Endothelial Cells

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