DISORDERS IN CELL CIRCUITRY ASSOCIATED WITH MULTISTAGE CARCINOGENESIS- EXPLOITABLE TARGETS FOR CANCER PREVENTION AND THERAPY

The development of a malignant tumor involves the progressive acquisit ion of mutations and epigenetic abnormalities in multiple genes that h ave highly diverse functions, Some of these genes code for pathways of signal transduction that mediate the action of growth factors, The en zyme protein kinase C plays an important role in these events and in t he process of tumor promotion, Therefore, we examined the effects of t hree inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calpho stin C, on human glioblastoma cells, These compounds inhibited growth and induced apoptosis; these activities were associated with a decreas e in the level of CDC2 and cyclin B1/CDC2-associated kinase activity, This may explain why the treated cells accumulated in G(2)-M. In a sep arate series of studies, we examined abnormalities in cell cycle contr ol genes in human cancer, We have found that cyclin D1 is frequently o verexpressed in a variety of human cancers, Mechanistic studies indica te that cyclin D1 can play a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis; introdu ction of an antisense cyclin D1 cDNA into either human esophageal or c olon cancer cells reverts their malignant phenotype; and overexpressio n of cyclin D1 can enhance the amplification of other genes, The latte r finding suggests that cyclin D1 can enhance genomic instability and, thereby, the process of tumor progression, Therefore, inhibitors of t he function of cyclin D1 may be useful in both cancer chemoprevention and therapy, We obtained evidence for the existence of homeostatic fee dback loops between cyclins D1 or E and the cell cycle inhibitory prot ein p27(Kip1). On the basis of these and other findings, we hypothesiz e that, because of their disordered circuitry, cancer cells suffer fro m ''gene addiction'' and ''gene hypersensitivity,'' disorders that mig ht be exploited in both cancer prevention and therapy.