title: Inhibition of rhabdomyosarcoma cell and tumor growth by targeting specificity protein (Sp) transcription factors.
abstract: 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.
authors: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
authors: Gayathri
authors: G
authors: Chadalapaka
authors: Indira
authors: I
authors: Jutooru
authors: Sandeep
authors: S
authors: Sreevalsan
authors: Satya
authors: S
authors: Pathi
authors: Kyounghyun
authors: K
authors: Kim
authors: Candy
authors: C
authors: Chen
authors: Lisa
authors: L
authors: Crose
authors: Corinne
authors: C
authors: Linardic
authors: Stephen
authors: S
authors: Safe
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009132:Muscles / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D017451:Receptors, Somatomedin / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051703:Sp Transcription Factors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C527276:CXCR4 protein, human; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D017451:Receptors, Somatomedin; D051703:Sp Transcription Factors; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid; D019859:Proto-Oncogene Proteins c-met; D020796:Receptor, Platelet-Derived Growth Factor alpha