Down-regulation of c-Myc following MEK/ERK inhibition halts the expression of malignant phenotype in rhabdomyosarcoma and in non muscle-derived human tumors

Marampon, Francesco; Ciccarelli, Carmela; Zani, Bianca M.

doi:10.1186/1476-4598-5-31

Cited by 129 publications

(74 citation statements)

References 39 publications

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“…1c). In the same western blot study, we also found that RR cells expressed a higher level of phosphorylated MYC S62 (i.e., p-MYC S62 ), the active form of MYC [12], than RU cells (Fig. 1c).…”

Section: Resultsmentioning

confidence: 64%

“…Anti-MYC (Y69) antibody (Abcam, Cambridge, MA) was used (1:300 dilution) in the immunohistochemistry assay, following the procedures described previously [12]. MYC (Y69) antibody (1:300 dilution) and anti-active β-catenin (8E7) antibody (Merck Millipore, Toronto, Ontario, Canada) (1:200 dilution) were used in immunofluorescence double staining.…”

Section: Methodsmentioning

confidence: 99%

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A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma

Zhang

Gupta

et al. 2016

J Hematol Oncol

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BackgroundWe have previously described the existence of two phenotypically distinct cell subsets in ALK-positive anaplastic large cell lymphoma (ALK + ALCL) based on their differential responsiveness to a Sox2 reporter (SRR2), with reporter-responsive (RR) cells being more tumorigenic and chemoresistant than reporter-unresponsive (RU) cells. However, the regulator(s) of RU/RR dichotomy are not identified. In this study, we aim to delineate the key regulator(s) of RU/RR dichotomy.MethodsJASPER motif match analysis was used to identify the putative factors binding to SRR2 sequence. SRR2 probe pull-down assay and quantitate real-time PCR were performed to analyze the regulation of Sox2 transcriptional activity by MYC. Methylcellulose colony formation assay, chemoresistance to doxorubicin and mouse xenograft study were performed to investigate the biological functions of MYC. PCR array and western blotting were executed to study related signaling pathways that regulate MYC expression. Immunofluorescence and immunohistochemistry assay were initiated to evaluate the expression of MYC and its correlation with its regulator by chi-square test analysis in human primary tumor cells.ResultsWe identified MYC as a potential regulator of RU/RR dichotomy. In support of its role, MYC was highly expressed in RR cells compared to RU cells, and inhibition of MYC substantially decreased the Sox2/SRR2 binding, Sox2 transcriptional activity, chemoresistance, and methylcellulose colony formation. In contrast, enforced expression of MYC in RU cells conferred the RR phenotype. The Wnt/β-catenin pathway, a positive regulator of MYC, was highly active in RR but not RU cells. While inhibition of this pathway in RR cells substantially decreased MYC expression and SRR2 reporter activity, experimental activation of this pathway led to the opposite effects in RU cells. Collectively, our results support a model in which a positive feedback loop involving Wnt/β-catenin/MYC and Sox2 contributes to the RR phenotype. In a mouse xenograft model, RU cells stably transfected with MYC showed upregulation of the Wnt/β-catenin/MYC/Sox2 axis and increased tumorigenecity. Correlating with these findings, there was a significant correlation between the expression of active β-catenin and MYC in ALK + ALCL primary tumor cells.ConclusionsA positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subset in ALK + ALCL.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0349-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 64%

Section: Methodsmentioning

confidence: 99%

A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma

Zhang

Gupta

et al. 2016

J Hematol Oncol

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“…Therefore, disruption of a balanced equilibrium between bHLH factors that dimerize with E-proteins could result in an excess of repressive rather than active complexes when the full activation of MyoD is required for terminal differentiation. Coexisting with these bHLH factors are multiple other inhibitors of MyoD activity, Pax3 and Pax7, and activated inhibitory signaling pathways, such as Ras (Marampon et al 2006;Langenau et al 2007) and Notch pathways (Kuroda et al 1999;Nofziger et al 1999).…”

Section: Discussionmentioning

confidence: 99%

MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state

et al. 2009

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Rhabdomyosarcomas are characterized by expression of myogenic specification genes, such as MyoD and/or Myf5, and some muscle structural genes in a population of cells that continues to replicate. Because MyoD is sufficient to induce terminal differentiation in a variety of cell types, we have sought to determine the molecular mechanisms that prevent MyoD activity in human embryonal rhabdomyosarcoma cells. In this study, we show that a combination of inhibitory Musculin:E-protein complexes and a novel splice form of E2A compete with MyoD for the generation of active full-length E-protein:MyoD heterodimers. A forced heterodimer between MyoD and the full-length E12 robustly restores differentiation in rhabdomyosarcoma cells and broadly suppresses multiple inhibitory pathways. Our studies indicate that rhabdomyosarcomas represent an arrested progress through a normal transitional state that is regulated by the relative abundance of heterodimers between MyoD and the full-length E2A proteins. The demonstration that multiple inhibitory mechanisms can be suppressed and myogenic differentiation can be induced in the RD rhabdomyosarcomas by increasing the abundance of MyoD: E-protein heterodimers suggests a central integrating function that can be targeted to force differentiation in muscle cancer cells.[Keywords: E2A; Musculin; MyoD; myogenesis; rhabdomyosarcoma] Supplemental material is available at http://www.genesdev.org.

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“…19–22 Deregulation of MAPK signaling pathway alone is usually not sufficient to induce a fully invasive phenotype, suggesting that additional ‘hits’ are required to promote the generation of metastatic cancer cells. 23,24 Notably, cooperation between transforming growth factor-β and sustained MAPK signaling pathways induces EMT and an invasive phenotype in cultured mammary epithelial cells. 25 HER-2/Neu is one of the major growth factor receptors overexpressed in approximately 25% of breast tumors that activate the MAPK signaling pathway and is strongly associated with poor patient survival.…”

Section: Introductionmentioning

confidence: 99%

The mitotic kinase Aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα+ breast cancer cells

et al. 2013

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In this study, we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces stabilization and accumulation of Aurora-A mitotic kinase that ultimately drives the transition from an epithelial to a highly invasive mesenchymal phenotype in estrogen receptor α-positive (ERα+) breast cancer cells. The transition from an epithelial- to a mesenchymal-like phenotype was characterized by reduced expression of ERα, HER-2/Neu overexpression and loss of CD24 surface receptor (CD24 –/low). Importantly, expression of key epithelial-to-mesenchymal transition (EMT) markers and upregulation of the stemness gene SOX2 was linked to acquisition of stem cell-like properties such as the ability to form mammospheres in vitro and tumor self-renewal in vivo. Moreover, aberrant Aurora-A kinase activity induced phosphorylation and nuclear translocation of SMAD5, indicating a novel interplay between Aurora-A and SMAD5 signaling pathways in the development of EMT, stemness and ultimately tumor progression. Importantly, pharmacological and molecular inhibition of Aurora-A kinase activity restored a CD24+ epithelial phenotype that was coupled to ERα expression, downregulation of HER-2/Neu, inhibition of EMT and impaired self-renewal ability, resulting in the suppression of distant metastases. Taken together, our findings show for the first time the causal role of Aurora-A kinase in the activation of EMT pathway responsible for the development of distant metastases in ERα+ breast cancer cells. Moreover, this study has important translational implications because it highlights the mitotic kinase Aurora-A as a novel promising therapeutic target to selectively eliminate highly invasive cancer cells and improve the disease-free and overall survival of ERα+ breast cancer patients resistant to conventional endocrine therapy.

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Down-regulation of c-Myc following MEK/ERK inhibition halts the expression of malignant phenotype in rhabdomyosarcoma and in non muscle-derived human tumors

Abstract: Background: Expression of c-myc proto-oncogene is inappropriate in a wide range of human tumors, and is a downstream target of Ras/Raf/ERK pathway, which promotes c-Myc stability by enhancing c-Myc expression and activity.

Cited by 129 publications

References 39 publications

A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma

A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma

MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state

The mitotic kinase Aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα+ breast cancer cells

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