ABSTRACT
C ancer is a complex multigenic disorder involving the perturbation of several different pathways that regulate cell differentiation, cell proliferation and cell survival. In theory, the process of macroautophagy (herein referred to as autophagy) may protect against cancer by sequestering damaged organelles, permitting cellular differentiation, increasing pro tein catabolism, and promoting autophagic cell death. Alternatively, autophagy may contrib ute to cancer by promoting the survival of nutrient-starved tumor cells. While there is some experimental evidence to support each of these possibilities, recent advances in understanding the molecular mechanisms of autophagy favor a model in which autophagy contributes to tumor suppression and in which defects in autophagy contribute to oncogenesis. Biochemical evidence in mammalian cells and genetic evidence in C. elegans suggests that autophagy is positively regulated by the PTEN tumor suppressor gene and negatively regulated by the onco genic Class I phosphatidylinositol 3-kinase signaling pathway. Furthermore, the mammalian APG gene, beclin 1, has tumor suppressor activity and maps to a tumor susceptibility locus that is commonly deleted in human breast and ovarian cancers. The genetic disruption of autoph agy control in human cancer provides new insights into understanding molecular mechanisms of oncogenesis. Such insights may foster the development of novel approaches to restore au tophagy in the chemoprevention or treatment of human malignancies.
