Autophagy as a Therapeutic Target in Gastrointestinal Cancer

Autophagy 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 autoph‐ agy. In general, the term “autophagy” indicates macroautophagy. Autophagy is mediated by double-membrane-bound structures called autophagosomes. During the autophagic process, cytoplasmic components are sequestered and engulfed by autophagosomes. Autophagosomes then fuse with lysosomes to form autolyso‐ somes where the sequestered components are digested by lysosomal hydrolases. Microtubule-associated protein 1 light chain 3 (LC3) is an autophagosomal ortholog of the yeast protein ATG8. Autophagy stimulates the upregulation of LC3 expres‐ sion, and a cytosolic form of LC3 (LC3-I) is conjugated to phosphatidylethanola‐ mine to form LC3-II which is recruited to autophagosomal membranes. Subsequently, LC3-II is degraded by lysosomal hydrolases after the fusion of auto‐ phagosomes with lysosomes. Therefore, LC3 is a specific marker of autophagosome formation. Additionally, beclin 1, the mammalian ortholog of the yeast protein ATG6, has been known to play a crucial role in autophagy. Beclin 1 acts in conjunc‐ tion with the phosphoinositide-3 kinase pathway to enhance the formation of the autophagic vacuole. Recently, autophagy has been reported to play roles in both cell death and survival. Autophagy is a multifaceted process, and alterations in autophagic signaling path‐ ways are frequently observed in cancer. Cancer is a disease caused by mutation, se‐ lection, 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. Apoptosis is regarded as the central mediator of programmed cell death in response to radia‐ tion and chemotherapy. Our previous report suggested that different cell-death pathways are activated in gastric and colorectal carcinomas and the extrinsic and © 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. intrinsic apoptotic pathways could be mutually regulated in gastric adenocarcino‐ mas. In contrast, in colorectal carcinomas, autophagy may function as a cellular guardian to prevent caspase-9-dependent apoptosis (intrinsic apoptotic pathway). LC3 positivity was less frequent in gastric adenocarcinomas than in colorectal ade‐ nocarcinomas. Therefore, we suggested that LC3 expression in colorectal carcino‐ mas is likely to aid cancer therapy, owing to its involvement in apoptosis and/or autophagy. In this chapter, we discuss the following: (1) the detection of autophagy using im‐ munohistochemistry, (2) autophagy and tumor suppression and/or progression, and (3) autophagy as a therapeutic target in gastrointestinal carcinomas.