Various growth and nutrient signaling pathways are associated with regulation of autophagy. Following inhibition of mTOR, the ULK/Atg13/FIP200 complex is activated and initiates autophagosome/phagophore formation. The class III PI3 kinase (Vps34)-Atg14L-Becn1 complex also regulates the autophagosome nucleation step. To expand the autophagosome membrane, two ubiquitin-like conjugation systems are required for conjugation of LC3 and Atg12 to phosphatidyl
ethanolamine (PE) on the autophagosome membrane and Atg5, respectively. Further, the Atg12-Atg5 conjugate interacts with Atg16, presumably located on the surface of the autophagosome membrane. The complete autophagosome fuses with the lysosome to form the autolysosome, and cargo molecules engulfed by autophagosomes are degraded by lysosomal hydrolases and recycled back to the cytoplasm. Several
pharmacological inhibitors (red) modulate distinct steps of autophagy. Some autophagy proteins with enzymatic activity (shown in green and yellow) could be crucial target proteins for modulation of autophagy. Points where
inhibitors could be potentially developed are shown as blank boxes. CQ, chloroquine.
The role of autophagy in cancer is context dependent. The role of autophagy as a tumor-suppressive process emerged in early studies showing that monoallelic deletion of the autophagy gene BECN1 is present in various human cancers, and that mice heterozygous for Becn1 (also known as Beclin1) develop multiple spontaneous
malignancies51, 52. Moreover, some gastric cancers carried nonsense mutations of ultraviolet radiation
resistance–associated gene (UVRAG), a Becn1-binding autophagy regulator53. A recent study found that mice with systemic mosaic deletion of atg5 or liver-specific deletion of atg7 have a high incidence of benign liver adenoma development, suggesting that autophagy suppresses tumor initiation54. Furthermore, p62, an autophagy substrate protein, accumulates in autophagy-deficient cells after metabolic stress, leading to increases in damaged mitochondria, oxidative stress and DNA damage through activation of nuclear factor-κB (NF-κB)55, 56.
In contrast, autophagy has been proposed to be a prosurvival process in cells exposed to metabolic stress. When growth factor–dependent cells are subjected to metabolic stress after growth factor deprivation, they use autophagy to generate additional bioenergetic substrates to support cell survival57. Similar results have been observed in established tumors: autophagy promotes cell survival in the center of the tumor, which is probably deprived of nutrients and oxygen58. In addition, cells genetically deficient in autophagy genes, such as BECN1 or atg5, are sensitive to metabolic stress59, 60. On the basis of recent immunohistochemical analysis of tumor samples, expression of mammalian homologs of Atg8, γ-aminobutyric acid A receptor–associated protein (GABARAP) and microtubule-associated protein 1 light chain 3 (LC3) is increased in various tumor tissues compared with normal tissues, and their expression correlates with tumor progression and poor therapeutic outcome61, 62. This indicates that autophagy is actively induced in advanced stages of tumorigenesis. Autophagy not only supports adaptation to the tumor microenvironment but also promotes cell survival under
certain oncogenic stresses, as illustrated in the examples below. Studies using genetically engineered mouse models of cancer indicate that autophagy is indispensable for tumor development and maintenance, regardless of nutrient availability. Targeted deletion of the autophagy gene RB1CC1 (also known as FIP200) leads to a substantial delay of mammary tumor progression in a mouse breast cancer model induced by the polyomavirus middle T (PyV-MT) oncogene63. Multiple studies have suggested that autophagy is required for RAS-induced transformation in vitro and RAS-driven tumorigenesis64, 65,
66
. Moreover, primary tumor cells and cell lines from
pancreatic tumors with KRAS mutations show elevated autophagy necessary for cancer cell growth in vitro67. Despite increasing evidence supporting the prosurvival role of autophagy in established cancer, the mechanisms whereby autophagy supports energy-demanding cancer cell metabolism are largely unknown. One hypothesis is that metabolites derived from autophagic degradation of cellular components might be used as bioenergetic and anabolic substrates for adaptation and growth of cancer cells. Indeed, metabolic analysis shows that autophagy is
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