Abstract B43: The utilization of extracellular proteins as nutrients is suppressed by mTORC1

To engage in growth and proliferation, cells require a continuous supply of precursors for macromolecular synthesis. Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. However, it was recently shown that Ras-induced macropinocytosis of extracellular proteins could reduce a transformed cell's dependence on extracellular amino acids. Here, we show that macropinocytosis and lysosomal catabolism of extracellular proteins can serve as a source of essential amino acids. Lysosomal degradation of internalized proteins can sustain cell survival and induce lysosomal recruitment and activation of mammalian target of rapamycin complex 1 (mTORC1), but fails to elicit significant cell accumulation. Surprisingly, we discovered that unlike its growth-promoting activity under amino acid-replete conditions, mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, by preventing consumption of extracellular proteins as nutrients, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics.Citation Format: Wilhelm Palm, Youngkyu Park, Kevin Wright, Natalya N. Pavlova, David A. Tuveson...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Alterations of Nutrient/Fuel Sensing in Cancer: Poster Presentations - Proffered Abstracts Source Type: research