Glucose Addiction of TSC Null Cells Is Caused by Failed mTORC1-Dependent Balancing of Metabolic Demand with Supply

Abstract

Summary The mTORC1 signaling pathway integrates environmental conditions into distinct signals for cell growth by balancing anabolic and catabolic processes. Accordingly, energetic stress inhibits mTORC1 signaling predominantly through AMPK-dependent activation of TSC1/2. Thus, TSC1/2-/- cells are hypersensitive to glucose deprivation and this has been linked to increased p53 translation and activation of apoptosis. Herein, we show that mTORC1 inhibition during glucose deprivation prevented not only the execution of death, but also induction of energetic stress. mTORC1 inhibition during glucose deprivation decreased AMPK activation and allowed ATP to remain high, which was both necessary and sufficient for protection. This effect was not due to increased catabolic activities such as autophagy, but rather exclusively due to decreased anabolic processes, reducing energy consumption. Specifically, TSC1/2-/- cells become highly dependent on glutamate dehydrogenase-dependent glutamine metabolism via the TCA cycle for survival. Therefore, mTORC1 inhibition during energetic stress is primarily to balance metabolic demand with supply.

mTOR-Dependent Cell Survival Mechanisms

“…Therefore, in this model, rapamycin's protective effect is the result of decreasing the bioenergetic demand in order to balance cellular metabolism with the supply of nutrients and to support the shift to a glutaminebased metabolism. This response is at least partially dependent on S6K1, but not on eIF4E, consistent with rapamycin's relative ineffectiveness at blocking 4E-BP1 phosphorylation (Feldman et al 2009;Thoreen et al 2009;Choo et al 2010). …”

“…In the absence of TSC2 function (e.g., in TSC2 2/2 cells), glucose deprivation results in cell death (Inoki et al 2003). Consistent with death being driven by mTORC1 pathways, rapamycin treatment prevents the death of TSC2 2/2 cells when glucose is unavailable in the culture medium (Inoki et al 2003;Choo et al 2010).…”

“…One possibility is that uncontrolled mTORC1 activity in starving cells continues to drive protein translation through 4E-BP1 and S6K1, and because translation is a major consumer of cellular energy, this exhausts the ATP reserves. However, rapamycin is only a partial mTORC1 inhibitor and relatively inefficient at suppressing translation in mammalian cells, suggesting that other rapamycinsensitive mTORC1 pathways might also be important (Feldman et al 2009;Thoreen et al 2009;Choo et al 2010).…”

“…Another more recent report finds that the hypersensitivity of TSC2-deficient cells to glucose deprivation is not linked to blocking apoptosis, to p53 levels, or to activating autophagy, but rather to rapamycin's ability to decrease metabolic consumption, maintain ATP levels, and suppress AMPK, thus preventing energetic stress (Choo et al 2010). These investigators also find that TSC2 2/2 cells deprived of glucose shift to using glutamine as a carbon source and that rapamycin fails to suppress cell death in the absence of glutamine.…”

Sugar-free approaches to cancer cell killing

“…Downstream of Akt, hyperactivation of mTOR, for instance, owing to the lack of tumor suppressor TSC1/2, promotes sensitivity to starvation. In this context, cells become unable to stop anabolism, and this leads to energy stress and cell death (Choo et al, 2010).…”