The utilization of extracellular proteins as nutrients is suppressed by mTORC1
Open accessAbstract
Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell's dependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source. Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1 but fails to elicit significant cell accumulation. Unlike its growth-promoting activity under amino-acid-replete conditions, we discovered that 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 nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics.
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In rapidly proliferating cells in cancer, serum albumin can be transported into cells and cell organelles, where it can be degraded to its component amino acids acting as building blocks.
“However, there is evidence in rapidly proliferating cells in cancer that serum albumin can be transported into cells and cell organelles, where it can be degraded to its component amino acids acting as building blocks.84, 85, 86, 87, 88”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [88]
The Results section on Ras-directed macropinocytosis shows that K-Ras-mutant mouse fibroblasts internalized albumin, degraded it in lysosomes, and used it to support proliferation during amino-acid starvation (page not available). A separate Results passage reports albumin-supported proliferation in Ras-mutant carcinoma cell lines, but only in leucine-free medium with mTOR inhibition; the claim omits those conditions and presents the mechanism more broadly in cancer cells. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSupplementation with physiological levels (20-30 mg/mL) of serum albumin enables proliferation of KRASG12D-transformed MEFs in the absence of leucine.
“supplementation of culture medium with physiological levels (20–30 mg/mL) of serum albumin enables proliferation of KRASG12D-transformed MEFs in the absence of an essential amino acid leucine”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Palm et al., 2015
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“We posit this to be due to mTOR-mediated growth suppression in cells that rely on extracellular proteins as an amino acid source (Palm et al., 2015), as in the case of Krasmutant cells (Bar-Sagi and Feramisco, 1986).”
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- Authors
- Palm, W., Park, Y., Wright, K., Pavlova, N. N., Tuveson, D. A., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Thompson, Craig B.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 162
- Issue
- 2
- Pages
- 259-270
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4506698
- OpenAlex
- W1829589101
- Cited by
- 457
- References
- 30
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 34 · 2023: 29 · 2022: 51 · 2021: 50 · 2020: 64 · 2019: 30 · 2018: 48 · 2017: 45 · 2016: 44 · 2015: 9
- FWCI
- 21.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Genentech Foundation
- Memorial Sloan-Kettering Cancer Center
- Cold Spring Harbor Laboratory
- Hope Funds for Cancer Research
- Foundation of Hope for Research and Treatment of Mental Illness
- National Institutes of Health (5p30ca045508-35)
- National Cancer Institute (5U01CA168409-3, P50CA101955, U10CA180944, P01CA104838, 5P30CA045508, U01CA168409, R01CA201318, P30-CA045508, 5P30CA45508-26, P30CA008748, R01CA190092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- mTORC1, extracellular proteins, macropinocytosis, amino acid metabolism, essential amino acids, lysosomal degradation, cell proliferation, nutrient deprivation, tumor vascularization, mTOR inhibitors, Ras signaling, glutamine addiction
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Albumins, Amino Acids, Animals, Cell Survival, Embryo, Mammalian, Fibroblasts, Lysosomes, Pinocytosis, Proteins, ras Proteins, Multiprotein Complexes, Cell Proliferation, Mice, Eukaryota, TOR Serine-Threonine Kinases
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