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Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and
I B Weinstein1, M Begemann, P Zhou
1Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Abstract:
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.
Insights
Protein kinase C inhibitors and cyclin D1 modulation show promise in cancer therapy. Targeting these pathways can inhibit glioblastoma cell growth and potentially reverse malignant phenotypes in various cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Malignant tumor development involves genetic mutations and epigenetic changes affecting diverse gene functions.
- Protein kinase C is crucial in signal transduction pathways and tumor promotion.
- Cyclin D1 overexpression is frequent in human cancers, contributing to carcinogenesis and genomic instability.
Purpose of the Study:
- To investigate the effects of protein kinase C inhibitors on human glioblastoma cells.
- To explore the role of cyclin D1 in cancer development and progression.
- To identify potential therapeutic targets for cancer chemoprevention and therapy.
Main Methods:
- Treatment of human glioblastoma cells with protein kinase C inhibitors (CGP 41251, RO 31-8220, calphostin C).
- Analysis of cell growth, apoptosis, CDC2, and cyclin B1/CDC2-associated kinase activity.
- Examination of cyclin D1 overexpression, antisense cyclin D1 cDNA introduction, and gene amplification in cancer cells.
- Investigation of feedback loops between cyclins and p27Kip1.
Main Results:
- Protein kinase C inhibitors reduced glioblastoma cell growth and induced apoptosis.
- Inhibitor treatment decreased CDC2 and cyclin B1/CDC2-associated kinase activity, leading to G2-M cell cycle arrest.
- Cyclin D1 overexpression enhanced cell transformation, tumorigenesis, and gene amplification, suggesting a role in genomic instability.
- Evidence for homeostatic feedback loops between cyclins and p27Kip1 was found.
Conclusions:
- Protein kinase C inhibitors demonstrate anti-cancer activity against glioblastoma.
- Cyclin D1 plays a critical role in carcinogenesis and tumor progression.
- Targeting cyclin D1 may offer therapeutic benefits for cancer prevention and treatment.
- Cancer cells' 'gene addiction' and 'gene hypersensitivity' present exploitable vulnerabilities for therapy.