The Role of Phorbol Ester Receptor Binding in Responses to Promoters by Mouse and Human Cells

Abstract

One of the major unanswered questions in carcinogenesis today concerns the rate-limiting steps that determine premalignant progression during the long latent period from the onset of carcinogen exposure until tumor appearance. Since tumor promoters apparently act to increase both the probability of occurrence and the rate of traversing events leading to malignancy, attempts to counter these promoter-induced events might offer a promising means of cancer prevention. In this connection, an understanding of the basis for resistance to tumor promoters could lead to an exploitable strategy. Our laboratory has developed the JB6 mouse epidermal cell model system for studying late-stage irreversible promotion of transformation by phorbol esters and other tumor promoters. We have recently described the isolation of promotion-resistant variants of JB6 cells which permit us to study the molecular and cellular basis for resistance (1,2). Since phorbol esters bind to specific cellular receptors and since resistance to a variety of hormones that also bind to specific receptors is associated with receptor deficiency (3), we have investigated whether the resistance of phorbol ester-resistant JB6 mouse cells can be attributed to a lack of phorbol diester receptors. This inquiry has been extended to phorbol ester-resistant variants of human hematopoietic cells.