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Apoptosis (2009) 14:376391 DOI 10.1007/s10495-008-0307-5
CELL DEATH AND DISEASE
The paradox of autophagy and its implication in cancer etiology and therapy
Avital Eisenberg-Lerner Adi Kimchi
Published online: 27 January 2009 The Author(s) 2009. This article is published with open access at Springerlink.com
Abstract Autophagy is a cellular self-catabolic process in which cytoplasmic constituents are sequestered in double membrane vesicles that fuse with lysosomes where they are degraded. As this catabolic activity generates energy, autophagy is often induced under nutrient limiting conditions providing a mechanism to maintain cell viability and may be exploited by cancer cells for survival under metabolic stress. However, progressive autophagy can be cytotoxic and autophagy can under certain settings substitute for apoptosis in induction of cell death. Moreover, loss of autophagy is correlated with tumorigenesis and several inducers of autophagy are tumor-suppressor genes. Thus, the relation of autophagy to cancer development is complex and depends on the genetic composition of the cell as well as on the extra-cellular stresses a cell is exposed to. In this review we describe the intricate nature of autophagy and its regulators, particularly those that have been linked to cancer. We discuss the multifaceted relation of autophagy to tumorigenesis and highlight studies supporting a role for autophagy in both tumor-suppression and tumor-progression. Finally, various autophagy-targeting therapeutic strategies for cancer treatment are presented.
Keywords Autophagy Cancer Tumorigenesis
Cell death Apoptosis
AbbreviationsAtg Autophagy related genesPI3K Phosphatidylinositol 3-kinase TOR Target of rapamycinPAS Pre-autophagosomal structure DAPk Death associated protein kinase
Introduction
Autophagy is a self-digestive process wherein bulk cytoplasmic components and intra-cellular organelles are sequestered in double membrane vesicles named auto-phagosomes. Upon maturation, autophagosomes fuse with lysosomes where their contents are degraded by the lysosomal proteases. The process of autophagy was initially described as a mechanism of cell survival under nutrient limiting conditions. Specically, the autophagic catabolic activity enables cells to restore sufcient energy levels in the absence of nutrients and consequently promotes viability [1]. This feature of autophagy is of particular importance during developmental processes, as it is suggested to maintain normal metabolism by providing an alternative cellular source for energy. Incidentally, deciency of Beclin 1 is embryonic lethal and Atg5 or Atg7 null mice fail to survive the neonatal starvation period and die perinatally [2, 3]. In addition, it...