Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in  selective toxicity for alveolar rhabdomyosarcoma cells

Massuda, Edmond; Dunphy, Edward J.; Redman, Rebecca; Schreiber, Jennifer J.; Nauta, Lauren E.; Barr, Frederic G.; Maxwell, Ian H.; Cripe, Timothy P.

doi:10.1073/pnas.94.26.14701

Cited by 35 publications

(12 citation statements)

References 39 publications

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“…HT-1080 and SKLMS1 cells were authenticated in May 2015. The Rhabdo CCL-136 cell line was derived from an embryonal rhabdomyosarcoma lacking t(2;13) and does not express PAX3-FKHR (44). This cell line was purchased from ATCC with valid STR in November 2014.…”

Section: Methodsmentioning

confidence: 99%

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Eisinger-Mathason

Mucaj

Biju

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.

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Section: Methodsmentioning

confidence: 99%

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Eisinger-Mathason

Mucaj

Biju

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Under the control of a cell type-or tumor-specific promoter, the DT-A gene has been tested in cancer therapy (15)(16)(17)(18)(19). This bacterial protein is highly toxic when introduced into the cytoplasm of eukaryotic cells.…”

Section: Discussionmentioning

confidence: 99%

“…We provide the evidence showing that, with the assistance of the engineered gene expression cassette, baculoviruses containing a cDNA encoding the A-chain of diphtheria toxin (DT-A; refs. [15][16][17][18][19] preferentially killed glioma cells in vitro and effectively inhibited the growth of glioma cells in the rat brain.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Baculovirus Containing the Diphtheria Toxin A Gene for Malignant Glioma Therapy

Wang

Yang

et al. 2006

Cancer Research

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Insect baculoviruses are capable of infecting mammalian glial cells in the central nervous system. We investigated in the current study the feasibility of using the viruses as toxin gene vectors to eliminate malignant glioma cells in the brain. We first confirmed that glioma cells were permissive to baculovirus infection, with variable transduction efficiencies at 100 viral particles per cell and ranging between 35% and 70% in seven human and rat glioma cell lines. We then developed a recombinant baculovirus vector accommodating the promoter of glial fibrillary acidic protein (GFAP) to minimize possible side effects caused by overexpression of a therapeutic gene in sensitive neurons. We placed the GFAP promoter into a baculovirus expression cassette, in which the enhancer of human cytomegalovirus immediate-early gene and the inverted terminal repeats of adeno-associated virus were employed to improve the relatively low transcriptional activity of the cellular promoter. This recombinant baculovirus significantly improved transduction in glioma cells, providing the efficiency in C6 rat glioma cells up to 96%. When used to produce the A-chain of diphtheria toxin intracellularly in a rat C6 glioma xenograft model, the baculovirus effectively suppressed tumor development. The new baculovirus vector circumvents some of the inherent problems associated with mammalian viral vectors and provides an additional option for cancer gene therapy. (Cancer Res 2006; 66(11): 5798-806)

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“…As described, strategies were developed to antagonize PAX3 ± FKHR expression with antisense oligonucleotides or to antagonize PAX3 ± FKHR function with an engineered PAX3 ± KRAB transcriptional repressor Bernasconi et al, 1996;Fredericks et al, 2000). Another therapeutic strategy involves transfer of a construct consisting of PAX binding sites that regulate expression of a toxinencoding gene (Massuda et al, 1997). Cell culture studies demonstrated that this construct is selectively toxic for cells expressing the PAX3 ± FKHR fusion.…”

Section: Molecular Diagnostic and Therapeutic Studies Of Arms Gene Fumentioning

confidence: 99%

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

2001

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The chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) are characteristic of alveolar rhabdomyosarcoma, a pediatric soft tissue cancer related to the striated muscle lineage. These translocations rearrange PAX3 and PAX7, members of the paired box transcription factor family, and juxtapose these genes with FKHR, a member of the fork head transcription factor family. This juxtaposition generates PAX3 ± FKHR and PAX7 ± FKHR chimeric genes that are expressed as chimeric transcripts that encode chimeric proteins. The fusion proteins, which contain the PAX3/PAX7 DNA binding domain and the FKHR transcriptional activation domain, activate transcription from PAX-binding sites with higher potency than the corresponding wild-type PAX proteins. This increased function results from the insensitivity of the FKHR activation domain to inhibitory e ects of N-terminal PAX3/PAX7 domains. In addition to altered function, the fusion products are expressed in ARMS tumors at higher levels than the corresponding wild-type PAX products due to two distinct mechanisms. The PAX7 ± FKHR fusion is overexpressed as a result of in vivo ampli®cation while the PAX3 ± FKHR fusion is overexpressed due to a copy number-independent increase in transcriptional rate. Finally, though FKHR subcellular localization is regulated by an AKTdependent pathway, the fusion proteins are resistant to these signals and show exclusively nuclear localization. Therefore, these translocations alter biological activity at the levels of protein function, gene expression, and subcellular localization with the cumulative outcome postulated to be aberrant regulation of PAX3/PAX7 target genes. This aberrant gene expression program is then hypothesized to contribute to tumorigenic behavior by impacting on the control of growth, apoptosis, di erentiation and motility. Oncogene (2001) 20, 5736 ± 5746.

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Regulated expression of the diphtheria toxin A chain by a tumor-specific chimeric transcription factor results in selective toxicity for alveolar rhabdomyosarcoma cells

Cited by 35 publications

References 39 publications

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Recombinant Baculovirus Containing the Diphtheria Toxin A Gene for Malignant Glioma Therapy

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

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