Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death

Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death

The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal-induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS-mediated cell death. Taken together, these findings illustrate the systems-level cross-talk between metabolism and signaling in the maintenance of cancer cell homeostasis.

From the discussion section:

The reprogramming of cellular metabolism during oncogenesis has attracted considerable recent attention, even being named one of the ‘emerging’ hallmarks of cancer (Hanahan and Weinberg, 2011). The metabolic reprogramming that helps satisfy the voracious appetite of tumor cells for biosynthetic precursors can also render cells exquisitely sensitive to nutrient deprivation (e.g., glucose and glutamine; Elstrom et al, 2004; Yuneva et al, 2007; Aykin-Burns et al, 2009; Yang et al, 2009).

Many doctors and researchers now advocate dietary carbohydrate restriction in cancer treatment, and this paper shows that glucose deprivation can cause cancer cells to die.


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