Increased radioresistance of ejras‐transformed human osteosarcoma cells and its modulation by lovastatin, an inhibitor of p21^ras isoprenylation

Abstract

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.

Statins are potential anticancerous agents (Review)

“…Furthermore, decreased risks of prostate cancer mortality and all-cause mortality were reported in patients who used statins prior to diagnosis [hazard ratio (HR), 0.55, 95% CI, 0.41-0.74; and HR, 0.66, 95% CI, 0.53-0. 81, respectively]. The results were higher compared to those obtained from patients who initiated the treatment only after diagnosis (HR, 0.82, 95% CI, 0.71-0.96; and HR, 0.91, 95% CI, 0.82-1.01, respectively) (38).…”

“…The late G1 and G2-M phases are most sensitive to radiation therapy; therefore, statins potentially sensitized cells to radiation in the late G1 phase (80,81). The antitumor effect of lovastatin as a radiosensitizer on b-cell rat lymphoma (L-TACb) was higher than that of individual therapy (82).…”

Farnesyltransferase inhibitor (L-744,832) restores TGF-β type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2

“…These types of mutations are commonly identified in the carcinomas of the pancreas and colon. In addition to ras oncogene transformation potential, the oncogenic ras expression often causes increased radiation resistance in many tumor cell types (Bruyneel et al, 1993;Hermens and Bentvelzen, 1992;Miller et al, 1993). Inhibiting oncogenic ras activity could reduce the resistance of tumor cells to radiation.…”

Identification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cells

“…Activation of protooncogenes, such as H-Ras, and inactivation of tumor suppressor genes, including p53, are involved in HN carcinogenesis (Je eries and Foulkes, 2001). In addition to their role in oncogenesis, expression of transforming oncogenes has been shown to confer cellular radio-and/ or chemo-resistance (Kasid et al, 1989;Miller et al, 1993;Miura et al, 1997). The development of HNSCC is accompanied by genetic and epigenetic changes including loss of heterozygosity, gene inactivation by methylation, and/or gene ampli®cation, all of which can alter gene function (Bishop and Schiestl, 2001).…”