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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.

AbstractBACKGROUND 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.
AuthorsH Hagiwara, H Sato, Y Ohde, Y Takano, T Seki, T Ariga, N Hokaiwado, M Asamoto, T Shirai, Y Nagashima, T Yano
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 153 Issue 7 Pg. 1373-81 (Apr 2008) ISSN: 0007-1188 [Print] England
PMID18264126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimetabolites, Antineoplastic
  • Connexins
  • RNA, Messenger
  • RNA, Small Interfering
  • connexin 32
  • Decitabine
  • Azacitidine
Topics
  • Animals
  • Antimetabolites, Antineoplastic (pharmacology)
  • Azacitidine (analogs & derivatives, pharmacology)
  • Carcinoma, Renal Cell (drug therapy, genetics)
  • Cell Line, Tumor
  • Connexins (drug effects, genetics)
  • Decitabine
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • RNA, Messenger (drug effects, metabolism)
  • RNA, Small Interfering (pharmacology)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation (drug effects)
  • Xenograft Model Antitumor Assays

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