ONCOGENE EXPRESSION AND CELLULAR RADIATION-RESISTANCE - A MODULATORY ROLE FOR C-MYC

Background: Being able to predict the response of tumors to radiation therapy would improve the decision-making process involved in choosing treatment options for cancer. Expression of certain oncogenes and/or inactivation of tumor suppressor genes has been shown to alter cellula r radiation responses; however, it is still not clear what marker or c ombination of markers would best indicate a radioresistant tumor, or w hether such screening would be clinically useful. Current choices of m arkers are derived mainly from in vitro studies on cell survival after irradiation. In general, expression of transforming oncogenes increas es cellular radioresistance. This was also demonstrated in this study for v-abl, bcr-abl, v-Hal-ras, v-mos, and v-fes expressed in rat-1 cel ls. There are, however, conflicting data. Some of the discrepancies ma y in part be due to interactions between the oncogene-activated signal s and other intrinsic or activated pathways. One downstream pathway th at is required for oncogene-induced transformation involves c-myc. The re is evidence that in some systems myc expression can potentiate ras- induced radiation resistance. Myc may therefore play an important role in determining tumor radioresistancy in the context of other oncogene s. Methods and Results: In this study, the role of c-myc in modulating intrinsic and oncogene-induced cellular radiation responses was inves tigated in more detail. Retroviral vectors were used to express c-myc and dominant negative mutant c-myc genes in rat 1 cells, with and with out ca-transfection of v-abl as measured by clonogenic assay, rat 1. C ells infected with c-myc or v-abl were more resistant to irradiation t han neo-transfected cells or control cells; however, cells doubly infe cted were not resistant, even though they had an increased transformat ion index. This indicates that transformation-related events per se do not necessarily lead to radiation resistance. It also suggests that t he effects of c-myc on radioresistance may depend on what other pathwa ys are activated. This conclusion was strengthened by the finding that expression of a dominant negative c-myc (dn-myc) mutant gene blocked v-abl-induced radiation resistance, but on its own made rat-1 cells mo re resistant to radiation. Conclusions: The apparently contradictory e ffects of c-myc in either enhancing or reducing radioresponsiveness ma y be explained by the dualistic roles of c-myc in promoting signal tra nsduction pathways resulting in either cell proliferation or death, de pending on what other pathways are activated, The studies indicate tha t it will be difficult to predict tumor response to radiation purely b y examining expression of transforming oncogenes and it is likely that a number of markers will need to be examined to derive a reliable ind ication of tumor radiation response.