Protection against malignant conversion in SENCAR mouse skin by all trans retinoic acid: inhibition of the ras p21-processing enzyme farnesyltransferase and Ha-ras p21 membrane localization.
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.
Agarwal
R
R
Department of Dermatology, University Hospitals of Cleveland, Case Western Reserve University, OH 44106-5028, USA.
Mohan
R R
RR
Ahmad
N
N
Mukhtar
H
H
D019883:Alkyl and Aryl Transferases; D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003600:Cytosol / Q000378:metabolism; D004224:Diterpenes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D010212:Papilloma / Q000201:enzymology / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D012867:Skin / Q000201:enzymology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D013729:Terpenes; D013755:Tetradecanoylphorbol Acetate; D014166:Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D004224:Diterpenes; D004791:Enzyme Inhibitors; D013729:Terpenes; C011309:mezerein; D014212:Tretinoin; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D016283:Proto-Oncogene Proteins p21(ras); D013755:Tetradecanoylphorbol Acetate