Hindawi Publishing Corporation International Journal of Cell Biology Volume 2012, Article ID 317645, 14 pages doi:10.1155/2012/317645 Review Article Novel Insights into the Interplay between Apoptosis and Autophagy Hidemi Rikiishi Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan Correspondence should be addressed to Hidemi Rikiishi, riki@m.tains.tohoku.ac.jp Received 27 October 2011; Accepted 31 December 2011 Academic Editor: Lina Ghibelli Copyright © 2012 Hidemi Rikiishi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. For several decades, apoptosis has taken center stage as the principal mechanism of programmed cell death (type I cell death) in mammalian tissues. Autophagic cell death (type II) is characterized by the massive accumulation of autophagic vacuoles in the cytoplasm of cells. The autophagic process is activated as an adaptive response to a variety of extracellular and intracellular stresses, including nutrient deprivation, hormonal or therapeutic treatment, pathogenic infection, aggregated and misfolded proteins, and damaged organelles. Increasing evidence indicates that autophagy is associated with a number of pathological processes, including cancer. The regulation of autophagy in cancer cells is complex since it can enhance cancer cell survival in response to certain stresses, while it can also act to suppress the initiation of cancer growth. This paper focused on recent advances regarding autophagy in cancer and the techniques currently available to manipulate autophagy. 1. Introduction Current cancer therapies are based on the surgical removal of solid tumor masses, usually combined with a series of chemical (chemotherapy) or physical (radiotherapy) treat- ments; however, chemotherapy has reached a plateau of eﬃcacy as a treatment modality with the emergence of resistant tumors. Despite the wide variety of mechanisms, most new drugs are thought to ultimately induce apoptosis of tumor cells through mitochondrial and/or death-receptor pathways, although these pathways are often defective in cancer. More recently, other mechanisms of cell death have emerged as potential novel mechanisms for cancer therapies to induce cell death. Macroautophagy (hereafter referred to autophagy) is a eukaryotic, evolutionarily conserved homeostatic process in which organelles and bulk proteins are turned over by lysoso- mal activity [1]. Autophagy and apoptosis may be intercon- nected and even simultaneously regulated by the same trigger in tumor cells. In periods of metabolic stress, autophagy provides ATP and other macromolecules as energy sources to enable cell survival; however, if the intensity or duration of metabolic stress is excessive, cells may progress to autophagic programmed cell death, which is distinct from apoptosis [2]. In contrast, whether autophagy contributes to the antitumor eﬀect of chemotherapeutic drugs or to drug resistance is largely unknown. In addition, there is no current consensus on how to manipulate autophagy to improve clinical out- comes. This paper describes the role of autophagy with a particular focus on the roles of cytoplasmic organelles and presents newly recognized approaches to pharmacologically exploit these mechanisms for improved antitumor outcomes. 2. Autophagy Networks 2.1. Degradation System. Eukaryotic cells respond to changes in their environment and the intracellular milieu by alter- ing their anabolic and catabolic pathways. As one of the responses, living organisms from yeast to humans are capable of eating parts of themselves in order to survive. The so- called autophagy is a self-degradative process which ensures the regular turnover of cellular components by sequester- ing damaged organelles and misfolded proteins, targeting them for lysosomal degradation [3]. While the ubiquitin- proteasomal system is generally used for the degradation of