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Fig. 2. Differential response of normal and tumor cells to metabolic stress. Normal cells regulate cell growth in response to nutrient availability by modulating the activity of the PI 3-kinase pathway, which through mTOR promotes cell growth and downregulates the catabolic process of autophagy. In periods of starvation, normal cells downregulate mTOR, which slows cell growth, while upregulating autophagy to allow adaptation to metabolic stress. In contrast, tumor cells frequently acquire mutations that constitutively activate the PI 3-kinase pathway that efficiently promotes cell growth in the presence of nutrients. In starvation conditions, however, tumor cells inefficiently adapt to metabolic stress through the failure to downregulate cell growth and upregulate autophagy, which can result in apoptotic or necrotic cell death though metabolic catastrophe.
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