Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors.
We report here a cancer drug therapy use of a gene involved in Down's syndrome. Using bioinformatics approaches, we recently predicted Single Minded 2 gene (SIM2) from Down's syndrome critical region to be specific to certain solid tumors. Involvement of SIM2 in solid tumors has not previously been reported. Intrigued by a possible association between a Down's syndrome gene and solid tumors, we monitored SIM2 expression in solid tumors. Isoform-specific expression of SIM2 short-form (SIM2-s) was seen selectively in colon, prostate, and pancreatic carcinomas but not in breast, lung, or ovarian carcinomas nor in most normal tissues. In colon tumors, SIM2-s expression was seen in early stages. Antisense inhibition of SIM2-s expression in a colon cancer cell line caused inhibition of gene expression, growth inhibition, and apoptosis. The administration of the antisense, but not the control, oligonucleotides caused a pronounced inhibition of tumor growth in nude mice with no major toxicity. Our findings provide a strong rationale for the genes-to-drugs paradigm, establish SIM2-s as a molecular target for cancer therapeutics, and may further understanding of the cancer risk of Down's syndrome patients.
DeYoung
Maurice Phil
MP
Center for Molecular Biology and Biotechnology and Department of Biology, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431, USA.
Tress
Matthew
M
Narayanan
Ramaswamy
R
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics*; D029721:Drosophila Proteins; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use; D009857:Oncogenes; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D051792:Basic Helix-Loop-Helix Proteins; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C417032:SIM2 protein, human; C089449:sim protein, Drosophila