Many studies have shown that
all trans retinoic acid (RA) exhibits significant protective effects against mouse skin
tumor promotion and spontaneous as well as enhanced malignant conversion. In a recently completed study, we showed that under treatments in which
papillomas on SENCAR mouse skin are induced at low and high probabilities to convert to malignant
carcinomas, RA affords significant protection against both
tumor promotion and subsequent malignant conversion. More than 95% of these mouse skin
papillomas and
carcinomas have been shown to contain point mutation at the 61
codon of Ha-ras oncogene. The ras oncogene encodes a p21
protein that, in its mutated form, transforms mammalian cells only when p21 is at the inner surface of the plasma membrane, by a series of enzymatic reactions in which the initial step is catalyzed by
farnesyltransferase (FTase). In this study, we assessed whether the protective effect of RA against malignant conversion involves the inhibition of ras p21 processing in those
tumors that contain the activated ras oncogene. The FTase activity and the levels of cytosolic and membrane-bound Ha-ras p21 were determined in all
papillomas and
carcinomas obtained from
acetone- or RA-treated animals. No matter how the data were analyzed and what comparisons were considered, in all the protocols used, compared with controls,
papillomas and
carcinomas obtained from RA-treated groups showed significantly decreased (P < 0.01-0.001) FTase activity. Furthermore, the tissue samples from RA-treated groups in different protocols also showed significantly diminished membrane localization of Ha-ras p21, with a concomitant increase in cytosolic Ha-ras p21 levels. The analysis of these data also showed that in all the protocols used, the increased FTase activity and membrane localization of Ha-ras p21 were associated with the induction of
papillomas and their subsequent malignant conversion to
squamous cell carcinomas. Taken together, these results indicate a strong correlation between the inhibition of ras p21 farnesylation because of a decrease in FTase activity by RA and its protective effect against malignant conversion of
papillomas to
carcinomas. Based on the results of this study, it is tempting to suggest that clinical trials evaluating the preventive or therapeutic potential of
retinoids may be directed more toward those clinical
malignancies that are known to contain the activated ras oncogene.