Overexpressed NF-kappaB-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells.
The nuclear factor-kappaB (NF-kappaB) transcription factors play important roles in cancer development by preventing apoptosis and facilitating the tumor cell growth. However, the precise mechanisms by which NF-kappaB is constitutively activated in specific cancer cells remain largely unknown. In our current study, we now report that NF-kappaB-inducing kinase (NIK) is overexpressed at the pretranslational level in adult T-cell leukemia (ATL) and Hodgkin Reed-Sternberg cells (H-RS) that do not express viral regulatory proteins. The overexpression of NIK causes cell transformation in rat fibroblasts, which is abolished by a super-repressor form of IkappaBalpha. Notably, depletion of NIK in ATL cells by RNA interference reduces the DNA-binding activity of NF-kappaB and NF-kappaB-dependent transcriptional activity, and efficiently suppresses tumor growth in NOD/SCID/gammac(null) mice. These results indicate that the deregulated expression of NIK plays a critical role in constitutive NF-kappaB activation in ATL and H-RS cells, and suggest also that NIK is an attractive molecular target for cancer therapy.
Saitoh
Yasunori
Y
Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Yamamoto
Norio
N
Dewan
M Zahidunnabi
MZ
Sugimoto
Haruyo
H
Martinez Bruyn
Vicente J
VJ
Iwasaki
Yuki
Y
Matsubara
Katsuyoshi
K
Qi
Xiaohua
X
Saitoh
Tatsuya
T
Imoto
Issei
I
Inazawa
Johji
J
Utsunomiya
Atae
A
Watanabe
Toshiki
T
Masuda
Takao
T
Yamamoto
Naoki
N
Yamaoka
Shoji
S
D000818:Animals; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000209:etiology* / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D016539:Reed-Sternberg Cells / Q000201:enzymology / Q000473:pathology; D000097782:NF-kappaB-Inducing Kinase
D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000097782:NF-kappaB-Inducing Kinase