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- Title
Suppression of N-Ras by shRNA-expressing plasmid increases sensitivity of HepG2 cells to vincristine-induced growth inhibition.
- Authors
Sun, H. -x.; He, H. -w.; Zhang, S. -h.; Liu, T. -g.; Ren, K. -h.; He, Q. -y.; Shao, R. -g.
- Abstract
Oncogenic ras genes relate to the development of human cancers. In this study, we used a plasmid-mediated short-hairpin RNA (shRNA) targeting N-ras gene to combine with clinical drug vincristine (VCR) for the treatment of human hepatoma cells. Our results showed that anti-N-Ras shRNA expression vector (pCSH1-shNR) knocked down the target mRNA and protein. Higher efficacy on growth inhibition was observed when pCSH1-shNR was combined with VCR. This synergistic effect was associated with abrogation of VCR-induced overexpressions of P-glycoprotein and multidrug resistance-associated protein 1 by pCSH1-shNR through downregulations of N-Ras and total Ras. Western blot analysis showed that pCSH1-shNR-induced downregulations of N-Ras and total Ras were potentiated by VCR. Following Ras downregulation, phosphorylations of ERK1/2 and Akt were dramatically inhibited by combinatory treatment. The data showed that pCSH1-shNR-induced inhibition of nuclear factor-κB was enhanced by VCR. In addition, the combination of pCSH1-shNR and VCR synergistically inhibited the growth of human hepatoma HepG2 in vivo. Our findings suggested that combination of gene-specific therapeutics and appropriate chemotherapeutic agents might be a promising approach for the treatment of human hepatocellular carcinoma.Cancer Gene Therapy (2009) 16, 693–702; doi:10.1038/cgt.2009.14; published online 27 February 2009
- Subjects
RAS oncogenes; ONCOGENES; GUANOSINE triphosphatase genes; PLASMIDS; GLYCOPROTEINS
- Publication
Cancer Gene Therapy, 2009, Vol 16, Issue 9, p693
- ISSN
0929-1903
- Publication type
Article
- DOI
10.1038/cgt.2009.14