Directed antisense therapy confirms the role of protein kinase C-alpha in the tumorigenicity of pancreatic cancer
| Autor: | D W, Denham, M G, Franz, W, Denham, E E, Zervos, W R, Gower, A S, Rosemurgy, J, Norman |
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| Rok vydání: | 1998 |
| Předmět: |
Mice
Inbred BALB C DNA Complementary Protein Kinase C-alpha Carcinogenicity Tests Mice Nude Genetic Therapy Adenocarcinoma Survival Analysis DNA Antisense Gene Expression Regulation Enzymologic Gene Expression Regulation Neoplastic Isoenzymes Pancreatic Neoplasms Disease Models Animal Mice Tumor Cells Cultured Animals Humans RNA Messenger Protein Kinase C |
| Zdroj: | Surgery. 124(2) |
| ISSN: | 0039-6060 |
| Popis: | The level of expression of the alpha isoform of protein kinase C (PKC-alpha) has been shown to correlate inversely with the pathologic differentiation of human pancreatic cancers.We stably transfected a moderately differentiated pancreatic cell line (HPAC) to overexpress PKC-alpha and examined the survival rates compared with parent HPAC according to an orthotopic model. Next we used a PKC-alpha antisense oligonucleotide specifically to down-regulate this isoform in vitro and examine the effect of treatment in vivo again according to the orthotopic model.Animals implanted with the overexpressing cell line had a mortality rate almost twice that of those implanted with the parent cell line (P.01). Treatment with antisense oligonucleotide in increasing concentrations down-regulated PKC-alpha mRNA by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Animals treated with antisense oligonucleotide after orthotopic implantation of pancreatic cancer cells survived statistically longer than those treated with vehicle alone (P = .005). Treatment with a scrambled oligonucleotide also conferred a survival benefit compared with vehicle alone (P.01).Tumorigenicity of pancreatic cancer is related directly to PKC-alpha expression in vivo as demonstrated by decreased survival when overexpressed. PKC-alpha expression can be down-regulated directly (antisense) and indirectly (scrambled) in vitro, which subsequently confers a dramatic survival benefit in vivo. |
| Databáze: | OpenAIRE |
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