p53, Autophagy and Tumor Suppression

Abstract

Previously published online as an Autophagy E-publication: http://www.landesbioscience.com/journals/autophagy/abstract.php?id=2051 KEY WORDSp53, autophagy, tumor suppression, Beclin 1, mTOR, apoptosis, necrosis ABBREVIATIONS atg autophagy-related mTOR mammalian target of rapamycin Addenda p53, Autophagy and Tumor Suppression ABSTRACT Autophagy was recently established as a novel tumor suppression mechanism, which stimulated a wave of investigations that were aimed at understanding exactly how autophagy prevents tumorigenesis, as well as to determine to what extent autophagy is implicated in human cancers. Autophagy might exert its tumor suppression function at the subcellular level by removing defective cytoplasmic components, such as damaged mitochondria. In addition, it might function at the cellular level by helping in the orderly removal of damaged cells. Previous studies indicated that autophagy is compromised in human breast, ovarian and prostate cancers. Recent research revealed that autophagy is activated by p53, a critical tumor suppressor that is involved in most, if not all, tumorigenesis. This study places autophagy in a broader context of human cancers. Future work elucidating the role of autophagy in the p53 circuit and p53 function might provide more insight into tumorigenesis and targeted cancer chemotherapy. AUTOPHAGY AND TUMOR SUPPRESSIONThe role of autophagy in tumor suppression was first suggested by the fact that the Beclin 1 gene, the human orthologue of an essential yeast autophagy gene, atg6 (autophagyrelated), is commonly deleted in human breast, ovarian and prostate cancers. 1,2 In addition, a number of other autophagy genes are also localized in chromosomal regions that are frequently lost in human cancers. For example, MAP1LC3 (ATG8 homolog) is localized at 16q24.1, a locus that is frequently deleted in liver, 3,4 breast, 5 prostate 6 and ovarian 7,8 cancers, whereas HsGSA7 (ATG7 homolog) (3p25.2) is commonly deleted in lung cancers. 9 Conversely, functional analysis indicated that ectopic expression of Beclin 1 protein in breast cancer cells, such as MCF-7, increases autophagy levels and results in inhibition of cell proliferation, reduction of clonigenicity and tumorigenesis. 2 Finally, Beclin 1 heterozygous knockout mice exhibit reduced autophagy levels and develop various tumors, 10,11 providing genetic evidence that compromised autophagy plays a causal role in tumorigenesis. Together, these observations strongly support the view that autophagy is a bona fide tumor suppression mechanism.Exactly how autophagy suppresses tumor development is less clear. Autophagy is a membrane trafficking process leading to lysosomal degradation of cytoplasmic components, a process that is highly conserved from yeast to humans. 12,13 Autophagy might serve a surveillance function at the subcellular level by selectively removing damaged cytoplasmic components, in particular damaged mitochondria-the major intracellular source of ROS (reactive oxygen species) which could damage nuclear DNA, cause mutati...

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