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H E Gabbert - One of the best experts on this subject based on the ideXlab platform.
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modulation of invasive potential in different clonal subpopulations of a rat Rhabdomyosarcoma Cell line ba han 1 by differentiation induction
Clinical & Experimental Metastasis, 1993Co-Authors: Cd Gerharz, Marc Bracke, Marcus Mareel, H E GabbertAbstract:Three clonal subpopulation (A, B, C) isolated from the same Rhabdomyosarcoma of the rat and differing in their degree of spontaneous differentiation were tested for their invasive potential before and after differentiation induction with retinoic acid (RA), N-monomethylformamide (NMF) and sodium butyrate (NaBut). Invasive potential was analysed in anin vitro assay using embryonic chick heart fragments in organotypic culture. In standard culture medium, all three subpopulations were shown to be invasive, progressively replacing the chick heart fragments within 7–11 days after confrontation. After exposure to RA, NMF or NaBut, marked differences in the invasive potential of these subpopulations were, however, observed. Subpopulation C exhibited a pronounced decline in invasive potential, as evidence by a significant decrease (P = 0.005) in the proportion of chick heart fragments with advanced stages of invasion. This response, however, was confined to the differentiation-inducing agents RA and NaBut, which had also produced a marked increase in morphological and/or biochemical differentiation (P = 0.0001). In contrast, NMF, which had only minor effects on differentiation, failed to affect the invasive potential of subpopulation C. In subpopulation B, a transient inhibition of single Cell invasion became evident after exposure to RA, whereas NMF and NaBut failed to affect the invasive potential in spite of minor effects on differentiation. In the least differentiated subpopulation A, which was shown to be refractory to the differentiation-inducing effects of RA, NMF and NaBut, there was also no observation of any reduction of invasive potential. The results of our study demonstrate that differentiation-inducing agents can significantly reduce the invasive potential of malignant tumors, although marked differences of response are to be expected between the different subpopulations of a tumor.
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Retinoic acid induces myogenin synthesis and myogenic differentiation in the rat Rhabdomyosarcoma Cell line BA-Han-1C.
The Journal of cell biology, 1992Co-Authors: H H Arnold, Claus-dieter Gerharz, H E Gabbert, A SalminenAbstract:Two clonal rat Rhabdomyosarcoma Cell lines BA-Han-1B and BA-Han-1C with different capacities for myogenic differentiation have been examined for the expression of muscle regulatory basic helix-loop-helix (bHLH) proteins of the MyoD family. Whereas Cells of the BA-Han-1C subpopulation constitutively expressed MyoD1 and could be induced to differentiate with retinoic acid (RA), BA-Han-1B Cells did not express any of the myogenic control factors and appeared to be largely differentiation-defective. Upon induction with RA, BA-Han-1C Cells expressed also myogenin, in contrast to BA-Han-1B Cells which never activated any of the genes encoding muscle bHLH factors. The onset of myogenin transcription in BA-Han-1C Cells required de novo protein synthesis and DNA replication suggesting that RA probably did not act directly on the myogenin gene. Although MyoD1 was expressed in proliferating BA-Han-1C myoblasts, muscle-specific reporter genes were not activated indicating that MyoD was biologically inactive. However, transfections with plasmid expressing additional MyoD1 protein resulted in the transactivation of muscle genes even in the absence of RA. mRNA encoding the negative regulatory HLH protein Id was expressed in proliferating BA-Han-1C Cells and disappeared later after RA induction which suggested that it may be involved in the regulation of MyoD1 activity. The myogenic differentiation of malignant Rhabdomyosarcoma Cells strictly correlated with the activation of the myogenin gene. In fact, stable transfections of BA-Han-1C Cells with myogenin expressing plasmids resulted in spontaneous differentiation. Together, our results suggest that the transformed and undifferentiated phenotype of BA-Han-1C Rhabdomyosarcoma Cells is associated with the inactivation of the myogenic factor MyoD1 as well as lack of myogenin expression. RA alleviates the inhibition of myogenic differentiation, probably by activating MyoD protein and myogenin gene transcription. BA-Han-1B Cells did not respond to RA and the differentiated phenotype could not be restored by overexpression of MyoD1 or myogenin.
A Salminen - One of the best experts on this subject based on the ideXlab platform.
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Retinoic acid induces myogenin synthesis and myogenic differentiation in the rat Rhabdomyosarcoma Cell line BA-Han-1C.
The Journal of cell biology, 1992Co-Authors: H H Arnold, Claus-dieter Gerharz, H E Gabbert, A SalminenAbstract:Two clonal rat Rhabdomyosarcoma Cell lines BA-Han-1B and BA-Han-1C with different capacities for myogenic differentiation have been examined for the expression of muscle regulatory basic helix-loop-helix (bHLH) proteins of the MyoD family. Whereas Cells of the BA-Han-1C subpopulation constitutively expressed MyoD1 and could be induced to differentiate with retinoic acid (RA), BA-Han-1B Cells did not express any of the myogenic control factors and appeared to be largely differentiation-defective. Upon induction with RA, BA-Han-1C Cells expressed also myogenin, in contrast to BA-Han-1B Cells which never activated any of the genes encoding muscle bHLH factors. The onset of myogenin transcription in BA-Han-1C Cells required de novo protein synthesis and DNA replication suggesting that RA probably did not act directly on the myogenin gene. Although MyoD1 was expressed in proliferating BA-Han-1C myoblasts, muscle-specific reporter genes were not activated indicating that MyoD was biologically inactive. However, transfections with plasmid expressing additional MyoD1 protein resulted in the transactivation of muscle genes even in the absence of RA. mRNA encoding the negative regulatory HLH protein Id was expressed in proliferating BA-Han-1C Cells and disappeared later after RA induction which suggested that it may be involved in the regulation of MyoD1 activity. The myogenic differentiation of malignant Rhabdomyosarcoma Cells strictly correlated with the activation of the myogenin gene. In fact, stable transfections of BA-Han-1C Cells with myogenin expressing plasmids resulted in spontaneous differentiation. Together, our results suggest that the transformed and undifferentiated phenotype of BA-Han-1C Rhabdomyosarcoma Cells is associated with the inactivation of the myogenic factor MyoD1 as well as lack of myogenin expression. RA alleviates the inhibition of myogenic differentiation, probably by activating MyoD protein and myogenin gene transcription. BA-Han-1B Cells did not respond to RA and the differentiated phenotype could not be restored by overexpression of MyoD1 or myogenin.
Stephen Safe - One of the best experts on this subject based on the ideXlab platform.
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reactive oxygen species ros inducing triterpenoid inhibits Rhabdomyosarcoma Cell and tumor growth through targeting sp transcription factors
Molecular Cancer Research, 2019Co-Authors: Ravi Kasiappan, Indira Jutooru, Kumaravel Mohankumar, Keshav Karki, Alexandra Lacey, Stephen SafeAbstract:Methyl 2-trifluoromethyl-3,11-dioxo-18β-olean-1,12-dien-3-oate (CF3DODA-Me) is derived synthetically from glycyrrhetinic acid, a major component of licorice, and this compound induced reactive oxygen species (ROS) in RD and Rh30 Rhabdomyosarcoma (RMS) Cells. CF3DODA-Me also inhibited growth and invasion and induced apoptosis in RMS Cells, and these responses were attenuated after cotreatment with the antioxidant glutathione, demonstrating the effective anticancer activity of ROS in RMS. CF3DODA-Me also downregulated expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and prooncogenic Sp-regulated genes including PAX3-FOXO1 (in Rh30 Cells). The mechanism of CF3DODA-Me–induced Sp-downregulation involved ROS-dependent repression of c-Myc and cMyc-regulated miR-27a and miR-17/20a, and this resulted in induction of the miRNA-regulated Sp repressors ZBTB4, ZBTB10, and ZBTB34. The Cell and tumor growth effects of CF3DODA-Me further emphasize the sensitivity of RMS Cells to ROS inducers and their potential clinical applications for treating this deadly disease. Implications: CF3DODA-Me and HDAC inhibitors that induce ROS-dependent Sp downregulation could be developed for clinical applications in treating Rhabdomyosarcoma.
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inhibition of Rhabdomyosarcoma Cell and tumor growth by targeting specificity protein sp transcription factors
International Journal of Cancer, 2013Co-Authors: Gayathri Chadalapaka, Corinne M Linardic, Lisa E S Crose, Indira Jutooru, Sandeep Sreevalsan, Satya Pathi, Kyounghyun Kim, Candy Chen, Stephen SafeAbstract:Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are highly expressed in Rhabdomyosarcoma (RMS) Cells. In tissue arrays of RMS tumor cores from 71 patients, 80% of RMS patients expressed high levels of Sp1 protein, whereas low expression of Sp1 was detected in normal muscle tissue. The non-steroidal anti-inflammatory drug (NSAID) tolfenamic acid (TA) inhibited growth and migration of RD and RH30 RMS Cell lines and also inhibited tumor growth in vivo using a mouse xenograft (RH30 Cells) model. The effects of TA were accompanied by downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes in RMS Cells and tumors, and the role of Sp protein downregulation in mediating inhibition of RD and RH30 Cell growth and migration was confirmed by individual and combined knockdown of Sp1, Sp3 and Sp4 proteins by RNA interference. TA treatment and Sp knockdown in RD and RH30 Cells also showed that four genes that are emerging as individual drug targets for treating RMS, namely c-MET, insulin-like growth factor receptor (IGFR), PDGFRα and CXCR4, are also Sp-regulated genes. These results suggest that NSAIDs such as TA may have potential clinical efficacy in drug combinations for treating RMS patients.
Corinne M Linardic - One of the best experts on this subject based on the ideXlab platform.
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a method to culture human alveolar Rhabdomyosarcoma Cell lines as rhabdospheres demonstrates an enrichment in stemness and notch signaling
Biology Open, 2021Co-Authors: Katherine K Slemmons, Michael D Deel, Yitzu Lin, Kristianne M Oristian, Nina Kuprasertkul, Katia C Genadry, Pohan Chen, Jentsan Ashley Chi, Corinne M LinardicAbstract:ABSTRACT The development of three-dimensional Cell culture techniques has allowed cancer researchers to study the stemness properties of cancer Cells in in vitro culture. However, a method to grow PAX3-FOXO1 fusion-positive Rhabdomyosarcoma (FP-RMS), an aggressive soft tissue sarcoma of childhood, has to date not been reported, hampering efforts to identify the dysregulated signaling pathways that underlie FP-RMS stemness. Here, we first examine the expression of canonical stem Cell markers in human RMS tumors and Cell lines. We then describe a method to grow FP-RMS Cell lines as rhabdospheres and demonstrate that these spheres are enriched in expression of canonical stemness factors as well as Notch signaling components. Specifically, FP-RMS rhabdospheres have increased expression of SOX2, POU5F1 (OCT4), and NANOG, and several receptors and transcriptional regulators in the Notch signaling pathway. FP-RMS rhabdospheres also exhibit functional stemness characteristics including multipotency, increased tumorigenicity in vivo, and chemoresistance. This method provides a novel practical tool to support research into FP-RMS stemness and chemoresistance signaling mechanisms.
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abstract a04 genetic and pharmacologic inhibition of hes1 reduces yap1 expression impairing Rhabdomyosarcoma Cell growth
Molecular Cancer Research, 2020Co-Authors: Alexander R Kovach, Corinne M LinardicAbstract:Rhabdomyosarcoma (RMS) is a mesenchymal cancer with skeletal muscle histogenesis and the most common soft-tissue sarcoma of childhood. High-risk patient groups continue to have a poor survival ( Citation Format: Alexander R. Kovach, Corinne M. Linardic. Genetic and pharmacologic inhibition of HES1 reduces YAP1 expression, impairing Rhabdomyosarcoma Cell growth [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A04.
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human Rhabdomyosarcoma Cell lines for Rhabdomyosarcoma research utility and pitfalls
Frontiers in Oncology, 2013Co-Authors: Ashley Hinson, Rosanne Jones, Lisa E S Crose, Brian C Belyea, Frederic G Barr, Corinne M LinardicAbstract:Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Despite intergroup clinical trials conducted in Europe and North America, outcomes for high risk patients with this disease have not significantly improved in the last several decades, and survival of metastatic or relapsed disease remains extremely poor. Accrual into new clinical trials is slow and difficult, so in vitro Cell line research and in vivo xenograft models present an attractive alternative for preclinical research for this cancer type. Currently, 30 commonly used human RMS Cell lines exist, with differing origins, karyotypes, histologies, and methods of validation. Selecting an appropriate Cell line for RMS research has important implications for outcomes. There are also potential pitfalls in using certain Cell lines including contamination with murine stromal Cells, cross-contamination between Cell lines, discordance between the Cell line and its associated original tumor, imposter Cell lines, and nomenclature errors that result in the circulation of two or more presumed unique Cell lines that are actually from the same origin. These pitfalls can be avoided by testing for species-specific isoenzymes, microarray analysis, assays for subtype-specific fusion products, and short tandem repeat analysis.
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inhibition of Rhabdomyosarcoma Cell and tumor growth by targeting specificity protein sp transcription factors
International Journal of Cancer, 2013Co-Authors: Gayathri Chadalapaka, Corinne M Linardic, Lisa E S Crose, Indira Jutooru, Sandeep Sreevalsan, Satya Pathi, Kyounghyun Kim, Candy Chen, Stephen SafeAbstract:Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are highly expressed in Rhabdomyosarcoma (RMS) Cells. In tissue arrays of RMS tumor cores from 71 patients, 80% of RMS patients expressed high levels of Sp1 protein, whereas low expression of Sp1 was detected in normal muscle tissue. The non-steroidal anti-inflammatory drug (NSAID) tolfenamic acid (TA) inhibited growth and migration of RD and RH30 RMS Cell lines and also inhibited tumor growth in vivo using a mouse xenograft (RH30 Cells) model. The effects of TA were accompanied by downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes in RMS Cells and tumors, and the role of Sp protein downregulation in mediating inhibition of RD and RH30 Cell growth and migration was confirmed by individual and combined knockdown of Sp1, Sp3 and Sp4 proteins by RNA interference. TA treatment and Sp knockdown in RD and RH30 Cells also showed that four genes that are emerging as individual drug targets for treating RMS, namely c-MET, insulin-like growth factor receptor (IGFR), PDGFRα and CXCR4, are also Sp-regulated genes. These results suggest that NSAIDs such as TA may have potential clinical efficacy in drug combinations for treating RMS patients.
H H Arnold - One of the best experts on this subject based on the ideXlab platform.
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Retinoic acid induces myogenin synthesis and myogenic differentiation in the rat Rhabdomyosarcoma Cell line BA-Han-1C.
The Journal of cell biology, 1992Co-Authors: H H Arnold, Claus-dieter Gerharz, H E Gabbert, A SalminenAbstract:Two clonal rat Rhabdomyosarcoma Cell lines BA-Han-1B and BA-Han-1C with different capacities for myogenic differentiation have been examined for the expression of muscle regulatory basic helix-loop-helix (bHLH) proteins of the MyoD family. Whereas Cells of the BA-Han-1C subpopulation constitutively expressed MyoD1 and could be induced to differentiate with retinoic acid (RA), BA-Han-1B Cells did not express any of the myogenic control factors and appeared to be largely differentiation-defective. Upon induction with RA, BA-Han-1C Cells expressed also myogenin, in contrast to BA-Han-1B Cells which never activated any of the genes encoding muscle bHLH factors. The onset of myogenin transcription in BA-Han-1C Cells required de novo protein synthesis and DNA replication suggesting that RA probably did not act directly on the myogenin gene. Although MyoD1 was expressed in proliferating BA-Han-1C myoblasts, muscle-specific reporter genes were not activated indicating that MyoD was biologically inactive. However, transfections with plasmid expressing additional MyoD1 protein resulted in the transactivation of muscle genes even in the absence of RA. mRNA encoding the negative regulatory HLH protein Id was expressed in proliferating BA-Han-1C Cells and disappeared later after RA induction which suggested that it may be involved in the regulation of MyoD1 activity. The myogenic differentiation of malignant Rhabdomyosarcoma Cells strictly correlated with the activation of the myogenin gene. In fact, stable transfections of BA-Han-1C Cells with myogenin expressing plasmids resulted in spontaneous differentiation. Together, our results suggest that the transformed and undifferentiated phenotype of BA-Han-1C Rhabdomyosarcoma Cells is associated with the inactivation of the myogenic factor MyoD1 as well as lack of myogenin expression. RA alleviates the inhibition of myogenic differentiation, probably by activating MyoD protein and myogenin gene transcription. BA-Han-1B Cells did not respond to RA and the differentiated phenotype could not be restored by overexpression of MyoD1 or myogenin.