The RNA catabolite 7-methylguanine has been shown to inhibit queuine modification of tRNA in Chinese hamster embryo cells under conditions leading to in vitro transformation. Phorbol ester tumor promoters also induce queuine hypomodification of tRNA in normal human cells, and this effect was reported to be correlated directly to the appearance of an altered (transformed) cell phenotype. Based on this common macromolecular alteration, 7-methylguanine was evaluated for its ability to enhance the chemically induced transformation of cultured cells. Two-stage initiation-promotion experiments were undertaken with Chinese hamster embryo cells in vitro to compare the effects of 7-methylguanine to known tumor promoters subsequent to initiation with 3-methylcholanthrene. 7-Methylguanine was able to increase significantly the expression of type III foci as well as anchorage-independent growth, thereby confirming that it can act as a promoting agent in vitro. Methylated guanines that do not induce queuine hypomodification of tRNA were not capable of enhancing these characteristics of in vitro transformation. The results suggest that 7-methylguanine may be a natural, endogenous promoting agent, and that changes in queuine modification of tRNA may play a fundamental role in the promotion of carcinogenesis.
Supported by Grant R810714-02 (R. W. T.) from the Environmental Protection Agency and Grant P-30-CA-16058-12 (OSUCCC) from the National Cancer Institute, Department of Health and Human Services.