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Symposium 21: Beyond Apoptosis: Alternative Responses to Therapy in Tumor Cells

Apoptosis versus alternative cell death programs

Buck Institute for Age Research, Novato, CA

Abstract

SY21-4

Programmatic cell death (pcd) (1) is an important aspect of development, neoplasia, and degeneration, among other processes. Abnormalities of control of pcd may lead to disease states such as developmental defects, tumors, or neurodegenerative diseases. Genetic and biochemical studies of pcd have identified a set of morphologically and biochemically similar cell death pathways given the name apoptosis (2). Although the term apoptosis has often been used interchangeably with the term pcd, it has become clear that the morphological and biochemical descriptions of apoptosis are inadequate to describe all pcd (3). For example, certain developmental cell deaths, such as "autophagic" cell death (4–9) and "cytoplasmic" cell death, (4,7) do not resemble apoptosis; nor do cell deaths in some neurodegenerative diseases such as Huntington’s and amyotrophic lateral sclerosis (10–11), as well as some ischemia-induced cell deaths (13). The biochemical basis for these alternative forms of cell death remains largely unknown. Understanding the mechanisms for these forms has potentially important implications for the understanding of evolutionary aspects of cell death programs, developmental cell death, neurodegeneration, and cancer therapeutics. Our interest in alternative, non-apoptotic forms of pcd was triggered by the observation that the expression of neurodegeneration-associated proteins such as mutant huntingtin led to apoptosis in cultured neural cells, yet in vivo these same mutations resulted in neural cell death that did not display the characteristics of apoptosis (12,14). This observation was supported by the finding of a shift in the "apostat" such that extracts from fetal and immature rodent brains were found to trigger the caspase activation associated with apoptosis when cytochrome c was added, whereas similar extracts from adults showed no such effect (15). The question thus arose as to whether, in the absence of apoptotic activation, alternative programs of cell death may be activated. The initial approach taken to identify alternative forms of pcd was to identify receptors that induce cell death that fails to fulfill the criteria for apoptosis, and two such receptors were initially identified: the insulin-like growth factor I receptor (IGF1R) and NK1R, the neurokinin-1 receptor. These dissimilar receptors both mediate a non-apoptotic cell death program(s) that is transcription dependent, lacks caspase activation, lacks internucleosomal DNA cleavage, lacks morphological hallmarks of apoptosis such as nuclear fragmentation, is not inhibited by caspase inhibitors or Bcl-xL, and features swelling of the endoplasmic reticulum and mitochondria (12,16). This alternative, non-apoptotic cell death program was dubbed paraptosis. Morphologically similar forms of cell death have been described in development, in neurodegeneration (in transgenic models of both amyotrophic lateral sclerosis and Huntington’s disease), in excitotoxicity, and in some organisms whose origins predate the evolutionary appearance of caspases, such as Dictyostelium discoideum (12). In order to identify the mediators of paraptosis, we have taken a combination of approaches that includes site-directed mutagenesis, protein interaction studies, gene expression microarray studies, and proteomics studies. Site-directed mutagenesis studies have revealed that NK1R is capable of inducing paraptosis in the absence of G-protein-coupled signal transduction, but that ligand binding (by substance P) and the carboxyterminal region of NK1R are required. Similar studies of IGF1R have demonstrated a requirement for both the kinase domain and the carboxyterminal region. The genomics and proteomics studies identified, among other alterations, a requirement for Nur77. Overall, our results suggest a model for paraptosis as a cell death program that complements apoptosis and is activated by trophic factor hyperstimulation rather than trophic factor withdrawal. This model implies that one advantage of the paraptotic pathway may be to prevent autocrine loop-induced tumor formation; a corollary is that autocrine loop tumors would be predicted to demonstrate mutations in genes involved in the paraptotic pathway.