Induction of Apoptosis in Rhabdomyosarcoma Cells through Down-Regulation of PAX Proteins

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 23; pp. 13164 - 13169
• Main Authors: Bernasconi, Michele, Remppis, Andrew, Fredericks, William J., Rauscher, Frank J., Schafer, Beat W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 12.11.1996; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Animals; Apoptosis; B lymphocytes; Base Sequence; Biological Sciences; Cancer; Cell cycle; Cell death; Cell Division - drug effects; Cell lines; Cell Survival - drug effects; Cells; Cellular biology; Child; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 2; DNA-Binding Proteins - biosynthesis; Down regulation; Gene Expression Regulation, Neoplastic - drug effects; Genes; HEK293 cells; Homeodomain Proteins; Humans; Mice; Muscle Proteins - biosynthesis; Nerve Tissue Proteins - biosynthesis; Oligonucleotides, Antisense - pharmacology; Paired Box Transcription Factors; PAX3 Transcription Factor; PAX7 Transcription Factor; Proteins; Recombinant Fusion Proteins - biosynthesis; Rhabdomyosarcoma, Alveolar - genetics; Rhabdomyosarcoma, Alveolar - pathology; Rhabdomyosarcoma, Alveolar - physiopathology; Transcription Factors; Translocation, Genetic; Tumors; Viability
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.23.13164

The expression of a number of human paired box-containing (PAX) genes has been correlated with various types of tumors. Novel fusion genes encoding chimeric fusion proteins have been found in the pediatric malignant tumor alveolar rhabdomyosarcoma (RMS). They are generated by two chromosomal translocations t(2;13) and t(1;13) juxtaposing PAX3 or PAX7, respectively, with a forkhead domain gene FKHR. Here we describe that specific down-regulation of the t(2;13) translocation product in alveolar RMS cells by antisense oligonucleotides results in reduced cellular viability. Cells of embryonal RMS, the other major histiotype of this tumor, were found to express either wild type PAX3 or PAX7 at elevated levels when compared with primary human myoblasts. Treatment of corresponding embryonal RMS cells with antisense olignucleotides directed against the mRNA translational start site of either one of these two transcription factors similarly triggers cell death, which is most likely due to induction of apoptosis. Retroviral mediated ectopic expression of mouse Pax3 in a PAX7 expressing embryonal RMS cell line could partially rescue antisense induced apoptosis. These data suggest that the PAX3/FKHR fusion gene and wild-type PAX genes play a causative role in the formation of RMS and presumably other tumor types, possibly by suppressing the apoptotic program that would normally eliminate these cells.