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Cyclic AMP blocks expression of the c-sis gene in tumor cells
G R Harsh1, W M Kavanaugh, N F Starksen
1Department of Neurological Surgery, School of Medicine, University of California, San Francisco 94143-0724.
Abstract:
Some human tumor cell lines express the c-sis gene, the proto-oncogene of the transforming gene v-sis, and produce platelet-derived growth factor, which may contribute to carcinogenesis by autocrine or paracrine mechanisms. Here we demonstrate that c-sis expression in some human glioma and osteosarcoma cell lines can be blocked by agents that increase cellular cyclic adenosine monophosphate (cAMP). Forskolin, 8-bromocyclic AMP, cholera toxin, and prostaglandin E1 reduced c-sis mRNA in these cells by up to 90%. c-sis transcription rates were reduced by agents that increase cAMP; the stability of c-sis mRNA was unaffected. The possible therapeutic value of blocking the expression of tumor growth factor genes pharmacologically warrants further study.
Insights
Agents increasing cyclic adenosine monophosphate (cAMP) significantly reduce c-sis gene expression in human tumor cells. This finding suggests a potential therapeutic strategy for blocking tumor growth factors by targeting c-sis gene transcription.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The c-sis gene, a proto-oncogene, produces platelet-derived growth factor, potentially driving carcinogenesis via autocrine or paracrine pathways.
- Expression of c-sis and subsequent growth factor production is observed in certain human tumor cell lines, including gliomas and osteosarcomas.
Purpose of the Study:
- To investigate the effect of agents that increase cellular cyclic adenosine monophosphate (cAMP) on c-sis gene expression in human tumor cell lines.
- To determine if pharmacological modulation of cAMP levels can inhibit the expression of the c-sis gene and its associated growth factor.
Main Methods:
- Treatment of human glioma and osteosarcoma cell lines with agents known to increase intracellular cAMP levels, such as forskolin, 8-bromocyclic AMP, cholera toxin, and prostaglandin E1.
- Quantification of c-sis messenger RNA (mRNA) levels and assessment of c-sis gene transcription rates before and after treatment.
- Analysis of the stability of c-sis mRNA following treatment with cAMP-increasing agents.
Main Results:
- Agents that elevate cellular cAMP levels, including forskolin, 8-bromocyclic AMP, cholera toxin, and prostaglandin E1, markedly reduced c-sis mRNA levels by up to 90% in the studied cell lines.
- The reduction in c-sis mRNA was attributed to decreased transcription rates of the c-sis gene, not to altered mRNA stability.
- Specific agents demonstrated significant inhibition of c-sis gene expression, highlighting a molecular mechanism for its regulation.
Conclusions:
- Elevating intracellular cAMP levels effectively inhibits c-sis gene expression in human glioma and osteosarcoma cell lines.
- Pharmacological agents that increase cAMP show promise for blocking the expression of tumor growth factor genes, suggesting potential therapeutic applications in cancer treatment.
- Further research is warranted to explore the therapeutic potential of targeting c-sis gene expression pharmacologically for cancer therapy.