Increased radioresistance of EJras-transformed human osteosarcoma cells and its modulation by lovastatin, an inhibitor of p21ras isoprenylation

• Published in: International journal of cancer Vol. 53; no. 2; p. 302
• Main Authors: Miller, A C, Kariko, K, Myers, C E, Clark, E P, Samid, D
• Format: Journal Article
• Language: English
• Published: United States 21.01.1993
• Subjects: Animals; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Transformed; Female; Genes, ras - physiology; Humans; Lovastatin - pharmacology; Mice; Mice, Nude; Neoplasm Transplantation; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma - radiotherapy; Protein Prenylation - drug effects; Proto-Oncogene Proteins p21(ras) - drug effects; Proto-Oncogene Proteins p21(ras) - metabolism; Radiation Tolerance - drug effects; Radiation Tolerance - genetics; Tumor Cells, Cultured - metabolism; Tumor Cells, Cultured - radiation effects
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.2910530222

Alterations in ras oncogene expression have been associated with increased cellular resistance to ionizing radiation. As an extension of studies with murine cell models, we have now explored the radioresponses of human osteosarcoma (HOS) sub-clones that differ in their EJras expression. Quantitative analysis revealed a tight correlation between the amounts of ras-encoded mRNA and p21 produced, and the degree of cell radioresistance. Interestingly, treatment of the ras-transformed cells with lovastatin, an inhibitor of p21ras post-translational processing via the mevalonate pathway, markedly decreased their radioresistance. Under the experimental conditions used, lovastatin prevented the membrane association, but not the biosynthesis, of p21. The decline in radiation resistance following lovastatin treatment could not be attributed to perturbation of cholesterol metabolism or to non-specific cell-cycle effects. In agreement, lovastatin did not alter the radiation responses of control HOS cells that do not express EJras, or those with an activated met oncogene. The results indicate that elevation in ras gene expression can lead to increased radioresistance of human tumor cells. It appears, however, that p21ras membrane localization is critical for maintenance of the radioresistant phenotype, thus providing a target for pharmacological intervention.