Functional genome screen for therapeutic targets of osteosarcoma.
Osteosarcoma (OS) is the most frequent primary malignant bone tumor of children and young adults. Although the introduction of combined neoadjuvant chemotherapy has markedly improved survival, the outcome of OS patients with distant metastasis and/or poor response to chemotherapy is still unsatisfactory. Therefore there is a need to develop new therapeutic agents that suppress OS cell proliferation with higher efficacy. The protein kinases are a family of genes that play critical roles in various signaling pathways. Some cancer cells show addiction to constitutive activation of certain signaling pathways for proliferation and survival. To identify new drug targets for OS, we screened a panel of small interfering RNAs (siRNAs) that target 691 genes encoding human protein kinases and related proteins. We found that different constructs of siRNA specifically targeting polo-like 1 kinase (PLK1) significantly caused mitotic cell cycle arrest and subsequent apoptotic cell death in a variety of OS cell lines. siRNA targeting PLK1 also suppressed the growth of OS xenografts established in immunodeficient mice. Recently, phase I clinical trials of PLK1 chemical inhibitors have been reported. Our results indicate that PLK1 is a promising molecular target for pharmacologic intervention in OS.
Yamaguchi
Umio
U
Chemotherapy Division, National Cancer Centre Research Institute, Tokyo, Japan.
Honda
Kazufumi
K
Satow
Reiko
R
Kobayashi
Eisuke
E
Nakayama
Robert
R
Ichikawa
Hitoshi
H
Shoji
Ayako
A
Shitashige
Miki
M
Masuda
Mari
M
Kawai
Akira
A
Chuman
Hirokazu
H
Iwamoto
Yukihide
Y
Hirohashi
Setsuo
S
Yamada
Tesshi
T
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012516:Osteosarcoma / Q000235:genetics / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1