Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate.
NK cell neoplasms are lymphoid malignancies with an aggressive clinical course. In the present study, we analyzed gene expression profiling of NK cell neoplasms and attempted to identify important molecular pathways and new effective drugs. Pathway analysis of gene expression profiles suggested the important roles of the JAK-STAT pathway, NF-κB pathway or Wnt pathways in NK cell neoplasms. Notably, western blot analysis revealed that STAT3 was expressed and phosphorylated at a higher level in NK cell lines than in normal NK cells or other cell lines. These findings indicate the occurrence of JAK-STAT activation in NK cell neoplasms. Connectivity Map (CMAP) analysis of gene expression profiles identified candidate drugs against NK cell neoplasms. Among the drugs suggested by CMAP analysis, we focused on puromycin, phenoxybenzamine, LY294002, wortmannin, vorinostat and trichostatin A because they exhibited high enrichment scores. We added these drugs to NK cell lines and other cell lines. Among the drugs, vorinostat suppressed NK cell line proliferation at a significantly lower concentration compared to other cell lines. Suppression of the JAK-STAT pathway appeared to contribute to this effect. Vorinostat may be a good candidate for use in the therapy against NK cell neoplasms.
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
Kennosuke
K
Karube
Shinobu
S
Tsuzuki
Noriaki
N
Yoshida
Kotaro
K
Arita
Harumi
H
Kato
Miyuki
M
Katayama
Young-Hyeh
YH
Ko
Koichi
K
Ohshima
Shigeo
S
Nakamura
Tomohiro
T
Kinoshita
Masao
M
Seto
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053616:Janus Kinase 3 / Q000502:physiology; D007694:Killer Cells, Natural / Q000473:pathology*; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000502:physiology; D059467:Transcriptome; D000077337:Vorinostat
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077337:Vorinostat; C507933:JAK3 protein, human; D053616:Janus Kinase 3