Abstract
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.