Defective autophagy control by the p53 rheostat in cancer.
Review
Overview
abstract
Autophagy is a finely regulated, lysosomal catabolic pathway that contributes to the turnover of long-lived proteins and to the elimination of old/damaged organelles. Autophagy exerts bona fide oncosuppressive functions by: (1) limiting chromosomal instability; (2) reducing potentially mutagenic oxidative stress; and (3) restraining intratumoral necrosis and local inflammation. Defective autophagy constitutes a hallmark of cancer cells together with: (1) provision of autonomous growth signals;, (2) insensitivity to antiproliferative stimuli; (3) disabled apoptosis; (4) limitless replication; (5) production of angiogenic factors; (6) tissue invasion with metastasis; (7) avoidance of the immune response; and (8) enhanced anabolism. p53 is the best-known human oncosuppressor protein, and its genetic/epigenetic inactivation has been observed in more than 50% of all human cancers. p53 mostly mediates tumor suppression by transactivating pro-apoptotic and cell cycle arresting genes, but also by favoring mitochondrial apoptosis in a transcription-independent fashion, by modulating metabolic circuitries and by regulating autophagy. p53 mutations (or epigenetic changes) that simultaneously abolish its pro-apoptotic and autophagy-inhibitory functions behave as "multi-hit" events, as opposed to "single-hit" mutations that only affect the classical (pro-apoptotic and/or cell cycle-arresting) functions of the p53 system. We speculate that, in this latter case, additional genetic/epigenetic events resulting in disabled autophagy are likely to contribute to accelerated oncogenesis.
