Derangement of apoptosis in cancer

• Published in: The Lancet (British edition) Vol. 358; no. 9279; pp. 345 - 346
• Main Authors: Eichhorst, Sören T, Krammer, Peter H
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 04.08.2001; Elsevier Limited
• Subjects: Animals; Apoptosis; Cancer; Cells; Cytochrome; fas Receptor - metabolism; Humans; Ligands; Lymphoma; Medical research; Mice; Mitochondria - metabolism; Mutation; Neoplasms - etiology; Proteins; Receptors, Tumor Necrosis Factor - metabolism; Tumor necrosis factor-TNF; Tumorigenesis; Tumors
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(01)05584-2

Just as direct inhibition of apoptosis can contribute to tumorigenesis, so can prevention of activation of proapoptotic molecules. Downmodulation of the death receptor CD95 has been found in tumours in vivo-for example, in hepatocellular carcinoma.13 Reduced levels of CD95 may be due to mutations in the tumour suppressor p53, which regulates CD95 via an intronic enhancer element. Mutations in p53 are found widely in human tumours-eg, in 20-25% of breast tumours and in 90% of small-cell lung cancers. p53 also regulates several other proapoptotic genes at a transcriptional or post-translational level. One of these genes is Bax. As a member of the Bcl-2 family the Bax protein antagonises Bcl-2. Thus, when p53 is mutated several apoptotic pathways are damaged. A more newly discovered mechanism by which CD95 can be blocked is through proviability receptors on the cell surface, which inhibit CD95 directly without the need for de-novo protein synthesis. For example, I M Catlett and colleagues14 have reported that the binding of MHC class II receptors on B cells impairs CD95-induced apoptosis.