Abstract
Here we determined which radiation-responsive genes were altered in radioresistant CEM/IR and FM3A/IR variants, which showed higher resistance to irradiation than parental human leukemia CEM and mouse mammary carcinoma FM3A cells, respectively and studied if radioresistance observed after radiotherapy could be restored by inhibition of protein kinase A. The expressions of DNA-PKcs, Ku70/80, Rad51 and Rad54 genes that related to DNA damage repair, and Bcl-2 and NF-kappaB genes that related to antiapoptosis, were up-regulated, but the expression of proapototic Bax gene was down-regulated in the radioresistant cells as compared to each parental counterpart. We also revealed that the combined treatment of radiation and the inhibitor of protein kinase A (PKA) to these radioresistant cells resulted in synergistic inhibition of DNA-PK, Rad51 and Bcl-2 expressions of the cells, and consequently restored radiosensitivity of the cells. Our results propose that combined treatment with radiotherapy and PKA inhibitor can be a novel therapeutic strategy to radioresistant cancers.
Highlights
Radiation therapy is an effective modality for the treatment of many tumors (Rosen et al, 1999)
To establish the mechanism how cancer cells acquire radioresistant phenotype, the expression of a variety of genes com monly associated with responsiveness to radiation in CEM/ionizing radiation (IR) cells was determined by Western blot analysis and their cellular levels compared with those in CEM cells
In the radioresistant CEM/IR and FM3A/IR cells, the expressions of DNA-PKcs, Ku70/80, Rad51 and Rad54 genes that related to DNA damage repair, and concurrently
Summary
Radiation therapy is an effective modality for the treatment of many tumors (Rosen et al, 1999). Its therapeutic efficacy is often hindered by acquirement of radioresistant phenotype of cancer cells (Pirollo et al, 1997). Molecular events leading to the formation of a radioresistant phenotype in cancer cells treated with ionizing radiation (IR) have not been studied extensively. The deregulation of DNA damage repair (Ader et al, 2002), induction of cell cycle arrest (Kang et al, 2004; Vavrova et al, 2004) and apoptosis resistance (Snyder and Morgan, 2004; Soderlund et al, 2005) may be responsible for radioresistance, even though the mechanism of radioresistance is not fully understood. The proteins controlling the processes of repair of DNA double strand breaks (DSBs), cell cycle arrest and apoptosis after IR-induced DNA damage are attractive candidates for generating variation in radiosensitivity
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