Autophagy as a Therapeutic Target in Gastrointestinal Cancer

Abstract

Abstract"utophagy is a bulk protein and organelle degradation system and is an important homeostatic cellular recycling mechanism. The following kinds are the three types of autophagy macroautophagy, microautophagy, and chaperone-mediated autophagy. In general, the term autophagy indicates macroautophagy. "utophagy is mediated by double-membrane-bound structures called autophagosomes. During the autophagic process, cytoplasmic components are sequestered and engulfed by autophagosomes. "utophagosomes then fuse with lysosomes to form autolysosomes where the sequestered components are digested by lysosomal hydrolases. Microtubule-associated protein light chain LC is an autophagosomal ortholog of the yeast protein "TG . "utophagy stimulates the upregulation of LC expression, and a cytosolic form of LC LC -I is conjugated to phosphatidylethanolamine to form LC -II which is recruited to autophagosomal membranes. Subsequently, LC -II is degraded by lysosomal hydrolases after the fusion of autophagosomes with lysosomes. Therefore, LC is a specific marker of autophagosome formation. "dditionally, beclin , the mammalian ortholog of the yeast protein "TG , has been known to play a crucial role in autophagy. "eclin acts in conjunction with the phosphoinositide-kinase pathway to enhance the formation of the autophagic vacuole.Recently, autophagy has been reported to play roles in both cell death and survival. "utophagy is a multifaceted process, and alterations in autophagic signaling pathways are frequently observed in cancer. Cancer is a disease caused by mutation, selection, and genome instability in tumor tissues, and the role of autophagy in cancer is unclear.One anticancer treatment strategy is to trigger tumor-selective cell death. "poptosis is regarded as the central mediator of programmed cell death in response to radiation and chemotherapy. Our previous report suggested that different cell-death pathways are activated in gastric and colorectal carcinomas and the extrinsic and intrinsic apoptotic pathways could be mutually regulated in gastric adenocarcinomas. In contrast, in colorectal carcinomas, autophagy may function as a cellular guardian to prevent caspase--dependent apoptosis intrinsic apoptotic pathway . LC positivity was less frequent in gastric adenocarcinomas than in colorectal adenocarcinomas. Therefore, we suggested that LC expression in colorectal carcinomas is likely to aid cancer therapy, owing to its involvement in apoptosis and/or autophagy.In this chapter, we discuss the following the detection of autophagy using immunohistochemistry, autophagy and tumor suppression and/or progression, and autophagy as a therapeutic target in gastrointestinal carcinomas.