Many types of cells undergo apoptosis as part of the normal physiological process. An interruption in apoptosis is thought to be a primary cause of tumor growth. Two presentations concerning this subject were made at the 88th Annual Meeting of the American Association for Cancer Research (AACR).
In the first presentation, Stanley J. Korsmeyer, MD, of the Howard Hughes Medical Institute at Washington University School of Medicine in St. Louis, discussed a series of genes, B-cell lymphoma 2 (bcl-2), bax, bad, and abid, that regulate cell death. The bcl-2 protein has the novel function of blocking programmed cell death, extending the survival of cells normally destined to die. For example, mice that over-express bcl-2 progress to life-threatening lymphoma. According to Korsmeyer, bcl-2 does not act alone but duels with its counteracting twin, bax. When bax is in excess, cells execute the programed death command. However, when bcl-2 dominates, the process is interrupted and cells survive.
In studies of bcl-2-deficient mice, Dr. Korsmeyer found that the embryos developed normally. However, when the mice reached adulthood, bax predominated, leading to massive cell death of lymphocytes and the disappearance of lymphoid organs. In addition, the embryonic loss of kidney cells led to polycystic kidney disease, and the death of melanocytes caused hair hypopigmentation. When Dr. Korsmeyer studied bax-deficient mice, he found that bcl-2 predominated. These mice displayed cellular hyperplasia and aberrations in cell death during the development of the testes.
According to Dr. Korsmeyer, "bcl-2 represents an important control step in the common pathway of apoptosis present in all cells. Evidence indicating that it serves as a critical checkpoint includes its role in the generation of human disease, its importance in developmental cell death, and its selection as a site of interference by DNA viruses. Further study of the bcl-2 family holds the promise of improving our understanding of the pathway of programmed cell death and the aberrations in this process that result in malignancy."
A Second Study
In another study, Huachen Wei, MD, PhD, Associate Professor of Dermatology at the Mount Sinai School of Medicine in New York, and his colleagues evaluated methods of regulating apoptosis as a new approach to the understanding of ultraviolet-induced carcinogenesis. They hypothesized that apoptosis could be induced by stimulating the tumor suppressor gene p53 or by down-regulating the expression of the apoptosis suppressor gene bcl-2. The p53 gene is thought to suppress tumor growth through two mechanisms: by arresting cell growth at a specific phase in the cell cycle and by inducing apoptosis. Mutations in this gene are thought to be the most common genetic mutations in human cancers.
Using a cell line that expresses both p53 and bcl-2, the investigators found that ultraviolet B radiation (UVB) significantly induced the expression of p53 in a dose- and time-dependent manner. However, exposure to the equally cytotoxic dose of ultraviolet A radiation (UVA) produced no effects on p53 expression. On the other hand, UVA substantially down-regulated the expression of bcl-2, whereas exposure to the same level of UVB produced no change in the expression of bcl-2.
"Our results indicate that both UVA and UVB cause cell damage and induce apoptosis by completely separate mechanisms," said Dr. Wei. "Because mutations in p53 and over-expression of bcl-2 can result in human cancers, our findings suggest that ultraviolet radiation may provide a new approach for drug development," said Dr. Wei.