2 short-lived proteins, autophagy degrades and recycles long- lived proteins and organelles. After its discovery, autophagy was considered a kind of disposal mechanism aimed at recycling of cellular components [4], but now autophagy is implicated in more diverse physiological processes such as development, proliferation, remodeling, aging, tumor sup- pression, neurodegeneration, antigen presentation, innate immunity, regulation of organismal lifespan, and cell death [5]. In most of these situations, autophagy has both ben- eﬁcial and harmful eﬀects on cell functions. One aspect of this complexity probably reﬂects the dual role of autophagy, which is both cell-protective and -destructive. Autophagy can be a survival response in situations of stress, allowing the elimination of toxic metabolites, intracellular pathogens, and damaged proteins and organelles and providing energy and amino acids necessary for vital functions during metabolic stress; however, in some sense the induction of excessive autophagy can lead to cell death. In addition, autophagy provides signals for removal of apoptotic cells and genomic stability [6]. Hence, autophagy can be generally considered as a cell protector against various types of injuries or continuous cellular wear and tear and is expected to play a protective role in diverse types of cellular stress. Paradoxi- cally, autophagy can also lead to a form of nonapoptotic cell death, which is called type II programmed cell death [7]. Thus, autophagy could either promote cell death or protect cells from diverse types of injuries depending on the cellular and environmental context. 2.2. Signaling System. The serine/threonine kinase, mam- malian target of rapamycin (mTOR), is a major negative reg- ulator of autophagy. The phosphoinositide 3-kinase- (PI3K-) activated serine/threonine kinase Akt phosphorylates the mTOR repressor TSC2 (tuberous sclerosis complex 2), thus leading to activation of mTOR and subsequent blockade of expression and function of autophagy-inducing Atg proteins. In addition to Akt, one of the main mTOR regulators is AMP-activated protein kinase (AMPK), a principal energy- sensing intracellular enzyme activated in various cellular and environmental stress conditions. In response to increases in AMP/ATP ratio, AMPK preserves energy by switching oﬀ ATP-requiring processes, while switching on ATP-generating catabolic pathways. AMPK maintains energy homeostasis by inducing autophagy and blocking protein synthesis and cell proliferation mainly through phosphorylation of its down- stream target Raptor and consequent inhibition of mTOR. In addition to a major role of the AMPK/mTOR pathway in regulation of intracellular and whole body metabolism, recent ﬁndings point to its potential involvement in con- trolling proliferation, survival, and death of cancer cells [8]. Namely, pharmacological activation or overexpression of AMPK in a variety of cancer cell types caused an mTOR inhibition-associated cell cycle arrest and apoptotic death both in vitro and in vivo [9]. On the other hand, AMPK activity in certain conditions protected normal and cancer cells from metabolic stress and/or chemotherapy-induced apoptosis [10]. Autophagic digestion of intracellular proteins triggered by mTOR-downregulation in tumor cells seems to International Journal of Cell Biology play an important role both in AMPK-mediated cytotoxicity and cytoprotection [11, 12], the ﬁnal outcome possibly depending on the nature of the cytotoxic stimulus. The physiological role of autophagy in the mammalian system has been shown in several in vivo animal models. Disruption of the autophagic process leads to failure of cavitation during embryogenesis or accumulation of abnormal organelles such as mitochondria or endoplasmic reticulum (ER) in adult tissues [13, 14]. In addition to the physiological roles, dys- regulated autophagy has been suggested to play pathogenetic roles in a variety of disease processes, particularly when cellular stress is increased, which is probably because of the accumulation of damaged molecules and organelles. It has been suggested that the role of autophagy in degenerative changes is associated with ageing or diverse degenerative disorders [15]. 3. Programmed Cell Death The term programmed cell death refers to controlled or regulated forms of cell death associated with a series of biochemical and morphological changes. Programmed cell death is an evolutionarily conserved process to decide cell fate, which has therefore been drawing increasing attention in cancer treatment. Programmed cell death can be divided into several categories: type I (apoptosis), type II (autophagic cell death), and others (necrosis, senescence, and mitotic catastrophe). 3.1. Type I Programmed Cell Death. In type I, the typical morphology of apoptosis is largely the end result of caspase- mediated destruction of the cellular structure [16]. There are two core pathways inducing apoptosis: the extrinsic and intrinsic pathways. The extrinsic pathway is triggered by the Fas death receptor (DR), which is mainly dependent on the initiation of the combination between FasL and Fas. The intrinsic pathway is another process leading to apoptosis, in which mitochondria play a central role. When cells sense extracellular stimuli or intracellular signals, the outer mitochondrial membrane becomes permeable, releasing cytochrome c. The ER, lysosomes, and the trans- Golgi-network also play important roles [17]. Each organelle possesses sensors that detect speciﬁc alterations, locally activate signal transduction pathways, and emit signals that ensure interorganellar cross-talk. It is often assumed that apoptosis is initiated if the damage is too severe to be repaired, or if the time-scale for complete repair is too long. 3.2. Type II Programmed Cell Death. Autophagy has been associated with a particular mode of cell death that is charac- terized by the appearance of double- or multiple-membrane cytoplasmic vesicles engulﬁng bulk cytoplasm and/or cyto- plasmic organelles such as mitochondria and ER; however, many studies failed to demonstrate a causal link between autophagy and cell death. Autophagy is probably not an executor of cell death per se, but it is a required process in certain settings in combination with other prodeath signals. Cells undergoing autophagic cell death were engulfed by