Autophagy in cellular growth control

Abstract

Cell growth is regulated by two antagonistic processes: TOR signaling and autophagy. These processes integrate signals including growth factors, amino acids, and energy status to ensure that cell growth is appropriate to environmental conditions. Autophagy responds indirectly to the cellular milieu as a downstream inhibitory target of TOR signaling and is also directly controlled by nutrient availability, cellular energy status, and cell stress. The control of cell growth by TOR signaling and autophagy are relevant to disease, as altered regulation of either pathway results in tumorigenesis. Here we give an overview of how TOR signaling and autophagy integrate nutritional status to regulate cell growth, how these pathways are coordinately regulated, and how dysfunction of this regulation might result in tumorigenesis.

FIGURE 1. Interrelations between TOR complex signaling, autophagy, and cell growth control

TORC1 signaling promotes cell growth through its effects both on increasing cell proliferation and increasing cell size and potentially through its inhibitory effects on autophagy. TORC1 increases protein synthesis and cell size through intermediates such as 4E-BP and S6K; it promotes cell proliferation at least in part through its effects on cyclin and cyclin-dependent kinase (CKD) inhibitors. In contrast, autophagy is believed to inhibit cell growth at least in part by promoting protein and/or organelle turnover. In addition, autophagy may have indirect effects on inhibiting cell proliferation through promoting senescence. Additional, not yet defined, mechanisms may also contribute to the inhibitory effects of autophagy on cell proliferation. Note that the presence of growth factors, nutrients, and sufficient energy are all required for the full activation of TORC1 signaling, whereas the absence of any of these factors or other types of cellular stressors are sufficient to induce autophagy.

FIGURE 2. Coordinated regulation of TORC1 signaling and autophagy

Schematic diagram depicting the different inputs that contribute to the regulation of TORC signaling and autophagy and, ultimately, cell growth. Bold lines represent an activation or inhibition for which there is molecular evidence for a direct interaction. Thin lines represent activation steps that are likely indirect. Some activation steps which have not yet been demonstrated in mammlian systems cells are marked with a question mark.

FIGURE 3. Possible mechanisms by which impaired autophagy promotes tumorigenesis

(A) In normal tissues, autophagy functions to promote cell survival in response to a variety of cellular insults including viral infection, DNA damage, nutrient starvation, or misfolded proteins. If the stressor is irreparable, the cell has a number of mechanisms to prevent the proliferation of damaged cells including apoptotic cell death, non-apoptotic cell death, and senescence. (B) In autophagy-deficient tissues, a cell is unable to respond to stressors, and several mechanisms have been proposed to contribute to tumorigenesis. (1) Autophagy has a role in the induction of senescence (Young et al., 2009) and non-apoptotic cell death (Yu et al., 2004), so its loss may result in a decreased ability to execute these potential tumor suppressor mechanisms; (2) Decreased autophagy has also been shown to increase cell proliferation through as-of-yet unknown mechanisms (Fimia et al., 2007; Qu et al., 2003); (3) Decreased autophagy results in increased chromosomal instability and mutagenesis possibly through the accumulation of damaged organelles and increased ROS (Karantza-Wadsworth et al., 2007; Mathew et al., 2009; Mathew et al., 2007). In contrast, the upregulation of autophagy in established tumors may promote the survival of tumor cells in response to metabolic stress in the tumor microenvironment. In this figure, normal cells are depicted as light blue; cells with decreased autophagy that are hyperproliferative are depicted as dark blue; and transformed cells are depicted as red. In general, there is an inverse correlation between levels of autophagy and cell size (Hosokawa et al., 2006; Lum et al., 2005a) which is depicted in this figure; however, multiple factors other than levels of autophagy contribute to the increased nuclear/cytoplasmic ratio of tumor cells. Senescent cells display a large and flattened morphology.