PAX3-FKHR sensitizes human alveolar rhabdomyosarcoma cells to camptothecin-mediated growth inhibition and apoptosis.
Patients with alveolar rhabdomyosarcoma (ARMS) have poorer response to conventional chemotherapy and lower survival rates than those with embryonal RMS (ERMS). By high-throughput screening, we identified camptothecin as an ARMS-selective inhibitor. Camptothecin more efficiently inhibited proliferation and induced apoptosis in Rh30 (ARMS) than RD (ERMS) cells. Ectopic expression of the PAX3-FKHR (PF) fusion protein in RD cells significantly increased sensitivity, whereas siRNA knockdown of PF decreased sensitivity of Rh30 cells to camptothecin. The sensitization required a transcriptionally active PF, and camptothecin downregulated levels of PF protein. These findings suggest that it is feasible to develop agents that preferentially block the growth of ARMS.
Zeng
Fu-Yue
FY
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cui
Jimmy
J
Liu
Lingling
L
Chen
Taosheng
T
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
D000972:Antineoplastic Agents, Phytogenic; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D002166:Camptothecin