The development of a malignant
tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes that have highly diverse functions. Some of these genes code for pathways of signal transduction that mediate the action of
growth factors. The
enzyme protein kinase C plays an important role in these events and in the process of
tumor promotion. Therefore, we examined the effects of three inhibitors of
protein kinase C,
CGP 41251,
RO 31-8220, and
calphostin C, on human
glioblastoma cells. These compounds inhibited growth and induced apoptosis; these activities were associated with a decrease in the level of CDC2 and
cyclin B1/CDC2-associated
kinase activity. This may explain why the treated cells accumulated in G2-M. In a separate series of studies, we examined abnormalities in cell cycle control genes in human
cancer. We have found that
cyclin D1 is frequently overexpressed in a variety of human
cancers. Mechanistic studies indicate that
cyclin D1 can play a critical role in
carcinogenesis because: overexpression enhances cell transformation and
tumorigenesis; introduction of an antisense
cyclin D1 cDNA into either human esophageal or
colon cancer cells reverts their malignant phenotype; and overexpression of
cyclin D1 can enhance the amplification of other genes. The latter finding suggests that
cyclin D1 can enhance
genomic instability and, thereby, the process of
tumor progression. Therefore, inhibitors of the function of
cyclin D1 may be useful in both
cancer chemoprevention and
therapy. We obtained evidence for the existence of homeostatic feedback loops between
cyclins D1 or E and the cell cycle inhibitory
protein p27Kip1. On the basis of these and other findings, we hypothesize that, because of their disordered circuitry,
cancer cells suffer from "gene addiction" and "gene
hypersensitivity," disorders that might be exploited in both
cancer prevention and
therapy.