mTORC1 inhibits the lysosomal catabolism and utilization of extracellular proteins for cell growth.

  • Major finding: mTORC1 inhibits the lysosomal catabolism and utilization of extracellular proteins for cell growth.

  • Clinical relevance: mTOR inhibition enhances cancer cell proliferation in poorly vascularized tumor regions.

  • Impact: These data may explain the limited efficacy of mTOR inhibitor treatment in RAS-mutant cancers.

Despite a milieu of diverse extracellular bioenergetic substrates, mammalian cells primarily metabolize low–molecular weight nutrients such as glucose and amino acids under nutrient-replete conditions. Recent studies have shown that oncogenic RAS–driven macropinocytosis of extracellular proteins can provide a source of glutamine for cell proliferation. Palm and colleagues report that, whereas wild-type and KRASG12D mouse embryonic fibroblasts (MEF) lost viability in the absence of essential amino acids (EAA), supplementation with physiologic levels of albumin restored the viability of wild-type cells and allowed RAS-mutant cells to proliferate, supporting the idea that RAS-mediated macropinocytosis enables cells to utilize extracellular proteins to derive EAA. Inhibition of either lysosomal degradation or macropinocytosis suppressed the proliferation of KRASG12D MEFs in leucine-free, albumin-supplemented medium, implicating these processes in mediating extracellular protein uptake and supporting cell growth during EAA starvation. Macropinocytosis and lysosomal degradation of internalized proteins increased mTOR complex 1 (mTORC1) activation at lysosomal membranes in a RAG-dependent manner. Surprisingly, however, whereas inhibition of mTOR or knockdown of the mTORC1 component Raptor in nutrient-replete medium impaired cell proliferation, mTORC1 blockade enhanced proliferation in EAA-depleted, albumin-supplemented medium. Inhibition of mTORC1 did not elevate endocytosis of extracellular proteins, but increased lysosomal degradation of internalized albumin, indicating that mTOR suppresses lysosomal processing of internalized proteins via a pathway distinct from its function in regulating autophagy. Furthermore, treatment with the mTOR inhibitor rapamycin decreased growth in the outer vascularized regions of KRAS-induced pancreatic tumors, but increased proliferation in poorly vascularized regions, supporting the notion that mTORC1 negatively regulates extracellular protein–dependent cell growth in nutrient-deprived conditions. Overall, these data provide a mechanism by which mTOR inhibition may promote tumor growth in the nutrient-deprived tumor microenvironment and provide an explanation for the lack of efficacy of mTOR inhibitors as single-agent therapies in cancer patients.

Palm W, Park Y, Wright K, Pavlova NN, Tuveson DA, Thompson CB. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 2015 Jul 2 [Epub ahead of print].