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5‐Aza‐2′‐deoxycytidine suppresses human renal carcinoma cell growth in a xenograft model via up‐regulation of the connexin 32 gene
Author(s) -
Hagiwara H,
Sato H,
Ohde Y,
Takano Y,
Seki T,
Ariga T,
Hokaiwado N,
Asamoto M,
Shirai T,
Nagashima Y,
Yano T
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.17
Subject(s) - cancer research , demethylating agent , cell growth , cell culture , dna methylation , biology , microbiology and biotechnology , gene expression , connexin 32 , connexin , small interfering rna , transfection , chemistry , gene , gap junction , intracellular , genetics , biochemistry
Background and purpose: The connexin ( Cx ) 32 gene, a member of the gap junction gene family, acts as a tumour suppressor gene in human renal cell carcinoma (RCC) and is down‐regulated by the hypermethylation of CpG islands in a promoter region of the Cx gene. The current study investigated whether the restoration of Cx32 silenced by hypermethylation in RCC by a DNA demethylating agent could be an effective treatment against RCC. Experimental approach: Using nude mice bearing Caki‐1 cells (a human metastatic RCC cell line), the effects of 5‐aza‐2′‐deoxycytidine (5‐aza‐CdR), a DNA demethylase inhibitor, on Cx32 mRNA expression and tumour growth were examined by RT‐PCR, and by measuring tumour weight and volume. Cx32 expression in Caki‐1 tumours was inhibited by Cx32 short interfering (si) RNA, and the effect of siRNA on 5‐aza‐CdR‐dependent suppression of tumour growth in nude mice was evaluated. Key results: 5‐aza‐CdR treatment inhibited the growth of Caki‐1 cells in nude mice by 70% and increased 7‐fold the level of Cx32 mRNA. The intratumour injection of Cx32 siRNA almost totally inhibited the expression of Cx32 mRNA and significantly reduced the suppression of tumour growth in 5‐aza‐CdR‐treated nude mice. Conclusions and implications: 5‐aza‐CdR suppressed the growth of Caki‐1 tumours in a xenograft model, by restoring Cx32 expression. This finding suggests that treatment with 5‐aza‐CdR could be a new effective therapy against human metastatic RCC and that Cx32 could be a potential target for the treatment of RCC. British Journal of Pharmacology (2008) 153 , 1373–1381; doi: 10.1038/bjp.2008.17 ; published online 11 February 2008