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Review
. 2010 Oct 22;40(2):323-32.
doi: 10.1016/j.molcel.2010.10.004.

Cellular metabolic stress: considering how cells respond to nutrient excess

Kathryn E Wellen  1 , Craig B Thompson
Affiliations
Review

Cellular metabolic stress: considering how cells respond to nutrient excess

Kathryn E Wellen et al. Mol Cell. .

Abstract

Nutrient stress is generally considered from the standpoint of how cells detect and respond to an insufficient supply of nutrients to meet their bioenergetic needs. However, cells also experience stress as a result of nutrient excess, during which reactive oxygen species (ROS) production exceeds that required for normal physiological responses. This may occur as a result of oncogene activation or chronic exposure to growth factors combined with high levels of nutrients. As a result, multiple mechanisms have evolved to allow cells to detect and adapt to elevated levels of intracellular metabolites, including promotion of signaling and proliferation by ROS, amino acid-dependent mTOR activation, and regulation of signaling and transcription through metabolite-sensitive protein modifications. We discuss how each of these responses can contribute to the development and/or progression of cancer under conditions of cellular nutrient excess and their potential roles in linking chronic organismal over-nutrition (obesity) with cancer.

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Figures

Figure 1
Figure 1. Both nutrient deficiency and nutrient excess can cause cellular stress
Mitochondrial ROS production from the electron transport chain increases in response to either hypoxia or oncogene activation and nutrient excess. Other mitochondrial sources of ROS such as proline oxidase are also involved in stress responses. At low levels, ROS production is critical for normal physiological processes, such as proliferation and differentiation, through regulation of signaling. At higher levels, ROS can induce changes that promote the development of cancer, such as mutation of DNA, prolonged signaling, and activation of inflammatory pathways. High levels of ROS can also lead to irreversible damage to cellular components and cell death.
Figure 2
Figure 2. High levels of nutrient uptake induced by chronic growth factor signaling or oncogenic mutations cause cellular ROS stress and can contribute to cancer development through multiple mechanisms
Elevated mitochondrial or NADPH oxidase-dependent ROS production can contribute to cancer through multiple mechanisms, including DNA mutation, activation of inflammatory pathways, HIF activation, and promotion of pro-growth signaling. ER stress can also activate inflammatory pathways and regulate oxidative stress response. Increased glucose metabolism leading to changes in protein acetylation and O-GlcNAcylation can regulate signaling, transcription, and metabolism. Metabolic regulation of N-glycan branching modulates growth factor receptor surface expression and downstream signaling. Increased pro-growth signaling, HIF stabilization, or mutation resulting in oncogene activation can all promote increased glucose uptake and metabolism, leading to a vicious cycle of increased nutrient uptake, stress responses, and cancer promotion.
Figure 3
Figure 3. Metabolically-sensitive protein modifications can participate in cellular nutrient sensing
Production of acetyl-CoA for acetylation is regulated by ATP-citrate lyase (ACL), in a manner dependent on the availability of mitochondria-derived citrate. Both N-linked glycosylation and O-GlcNAcylation of proteins relies on production of UDP-GlcNAc by the hexosamine biosynthetic pathway.
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