Christopher French

Caspase-8  may be involved in various diseases including Huntington’s disease (HD), type two diabetes, autoimmune lymphoproliferative disease, arthritis, and cancer. HD is associated with increased HD gene product called huntingtin. Overexpression of this gene product induces apoptosis in cerebellar and striatal neurons. Patients with HD have increased activated caspase 8 in the affected regions of their brains. The mutated huntingtin does not bind huntingtin interacting protein-1 (Hip-1). Free Hip-1 which is in excess then binds and initiates the apoptotic cascade through capsase-8. Thus, modulation of the caspase-8 apoptotic cascade is an treatment strategy to patients with HD. Defects is caspase-8 may also be responsible for autoimmune lymphoproliferative syndrome (ALPS). Some ALPS patients have a mutation in their caspase 8 gene that reduces protein stability and diminishes the enzymatic activity of the caspase 8 protein. Thus, caspase-8 plays a very important role in the immune system. Caspase 8 may play a role in arthritic diseases such as rheumatoid arthritis (RA). Deregulation of apoptosis in osteoblasts and T cells in rheumatoid synovium is a hallmark of RA. RA macrophages have reduced Fas-induced apoptosis. Caspase 8 may also play a role in cancer, where it acts as a tumor suppressor. Caspase-8 has been found to be downregulated in pediatric tumors and neuroendocrine lung tumors. Mutations in the caspase 8 gene have also been reported in small cell lung carcinoma. Downregulation of caspase 8 may lead to increased resistance to chemotherapy and increased metastasis. Thus, capase-8 upregulation and its inhibition are both attractive strategies for treatment in various diseases processes.