Editors' ChoiceCell Biology

Differentiating between nutrient sources

Sci. Signal.  28 Jul 2015:
Vol. 8, Issue 387, pp. ec204
DOI: 10.1126/scisignal.aad0909

The kinase complex mTORC1 integrates signals from growth factors with the availability of nutrients to control cell growth and proliferation. When growth factors are present and free essential amino acids and glucose are abundant, mTORC1 is active and promotes growth and proliferation; when free amino acids are not abundant, mTORC1 is inhibited and cells rely on autophagy to provide nutrients for survival, and growth and proliferation are suppressed. Palm et al. found that mTORC1 also enables cells to distinguish between free amino acids and extracellular proteins as nutrient sources. Because albumin is the most abundant protein in the blood and interstitial fluids, the authors compared the effect of culture medium lacking glucose or essential amino acids with or without 3% albumin (an amount similar to that in the circulation) on the number of immortalized mouse embryo fibroblasts (MEFs) or MEFs with a constitutively active K-RasG12D. Albumin supplementation maintained cell numbers of both types of MEFs cultured in the absence of the essential amino acid leucine but not of glucose. Albumin even promoted proliferation of the K-RasG12D MEFs cultured in the absence of the essential amino acid leucine, but not when macropinocytosis or lysosome function was inhibited. Analysis of phosphorylation of mTORC1 targets showed that adding albumin to K-RasG12D MEFs that had been starved in medium lacking essential amino acids activated mTORC1, but activation required hours more than when starvation was followed by the addition of free essential amino acids. Restoration of either essential amino acids or albumin promoted the translocation of mTOR to lysosomes in the starved cells (based on immunofluorescence colocalization with lysosomal markers), but only albumin-induced recruitment of mTOR to lysosomes and activation of mTORC1 required macropinocytosis and lysosome function. Unexpectedly, inhibition of mTORC1—either pharmacologically or by knocking down essential components of the complex—increased the lysosome-mediated degradation of albumin and enhanced proliferation of MEFs with wild-type K-Ras or K-RasG12D cultured in leucine-free medium supplemented with albumin, but decreased proliferation in medium containing free essential amino acids. In a mouse model of pancreatic cancer driven by K-Ras and p53 mutations (KPC), treatment with the mTOR inhibitor rapamycin increased the number of proliferative (Ki-67–positive) tumor cells in poorly vascularized regions and reduced the number in the vascularized outer regions of the tumor. Thus, the effects of mTORC1 inhibition in cancer depend on the microenvironment of the tumor cell, which has implications for using mTORC1 inhibitors as cancer therapeutics.

W. Palm, Y. Park, K. Wright, N. N. Pavlova, D. A. Tuveson, C. B. Thompson, The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259–270 (2015). [PubMed]