Effective inhibition of cell growth and invasion of melanoma by combined suppression of BRAF (V599E) and Skp2 with lentiviral RNAi

Hidetoshi Sumimoto, Kenro Hirata, Shizuko Yamagata, Hiroyuki Miyoshi, Makoto Miyagishi, Kazunari Taira, Yutaka Kawakami

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

p27Kip1 that regulates the G1/S transition of cell cycle and inhibits Rho A signaling is frequently lost in several cancers leading to the deregulation of cell growth and cell motility. Mitogen-activated protein kinases (MAPK) regulate the export of p27Kip1 from nucleus to cytoplasm, followed by the degradation with proteases. Skp-2, a subunit of an SCF ubiquitin-protein ligase complex responsible for the ubiquitination of p27 Kip1, is upregulated frequently in several cancers, leading to the decrease of p27Kip1. We applied human immunodeficiency virus (HIV) lentivirus-mediated RNA interference (RNAi) to melanoma cells with the BRAF mutation (V599E) and overexpressed Skp-2 and found that the simultaneous suppression of these activated oncogenes resulted in the effective inhibition of in vitro cell growth and invasive ability of melanoma cells accompanied by the additional increase of p27Kip1. Our results suggest that gene therapy against melanoma with the enhanced MAPK and ubiquitin-proteasomal pathways could be a specific and effective therapeutic strategy for cancers.

Original languageEnglish
Pages (from-to)472-476
Number of pages5
JournalInternational Journal of Cancer
Volume118
Issue number2
DOIs
Publication statusPublished - 2006 Jan 15

Keywords

  • BRAF
  • RNA interference
  • Skp-2
  • lentivirus
  • p27

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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