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Evidence supporting a signal transduction pathway leading to the radiation-resistant phenotype in human tumor cells
1Department of Surgery, Stanford University Medical Center, California 94305-5328, USA.
Abstract:
A signal transduction pathway, involving oncogenes and their normal counterparts the proto-oncogenes, analogous to that for cell growth and differentiation has been proposed to lead to the phenotype of cellular radioresistance (RR). In this report we provide evidence demonstrating the existence of such a pathway by using antisense oligonucleotides (ASO) to reverse the RR phenotype. Utilizing ASO directed against the raf-1 gene, a central component of this proposed pathway, we were able to reverse the RR phenotype of human tumor cell lines having elevated HER-2 expression or a mutant form of Ha-ras, two genes upstream of raf-1 in signal transduction. Additionally, anti-ras ASO were able to radiosensitize HER-2 overexpressing cells. These results, which verify the presence of a signaling pathway leading to cellular RR, also have possible clinical implications for the use of ASO as a means to sensitize radioresistant tumors to radiation therapy.
Insights
Antisense oligonucleotides (ASO) targeting the raf-1 gene reversed radioresistance in cancer cells. This confirms a signaling pathway for cellular radioresistance and suggests ASO could sensitize tumors to radiation therapy.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- Cellular radioresistance (RR) is linked to signal transduction pathways involving oncogenes.
- A pathway analogous to cell growth and differentiation pathways has been proposed to cause RR.
Purpose of the Study:
- To provide evidence for a signal transduction pathway leading to cellular radioresistance.
- To investigate the potential of antisense oligonucleotides (ASO) to reverse the RR phenotype.
Main Methods:
- Utilized antisense oligonucleotides (ASO) targeting the raf-1 gene.
- Tested ASO efficacy on human tumor cell lines with elevated HER-2 expression or mutant Ha-ras.
- Assessed the ability of anti-ras ASO to radiosensitize HER-2 overexpressing cells.
Main Results:
- ASO directed against raf-1 reversed the radioresistance phenotype in tested cell lines.
- Elevated HER-2 expression or mutant Ha-ras, upstream of raf-1, were associated with RR.
- Anti-ras ASO demonstrated radiosensitizing effects on HER-2 overexpressing cells.
Conclusions:
- Confirmed the existence of a signaling pathway contributing to cellular radioresistance.
- Demonstrated that ASO can reverse the RR phenotype.
- Highlighted potential clinical applications of ASO for sensitizing radioresistant tumors to radiation therapy.