Title | Rac-Mediated Macropinocytosis of Extracellular Protein Promotes Glucose Independence in Non-Small Cell Lung Cancer. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Hodakoski C, Hopkins BD, Zhang G, Su T, Cheng Z, Morris R, Rhee KY, Goncalves MD, Cantley LC |
Journal | Cancers (Basel) |
Volume | 11 |
Issue | 1 |
Date Published | 2019 Jan 02 |
ISSN | 2072-6694 |
Abstract | Cancer cells can adapt to nutrient poor conditions by rewiring their metabolism and using alternate fuel sources. Identifying these adaptive metabolic pathways may provide novel targets for cancer therapy. Here, we identify a subset of non-small cell lung cancer (NSCLC) cell lines that survive in the absence of glucose by internalizing and metabolizing extracellular protein via macropinocytosis. Macropinocytosis is increased in these glucose independent cells, and is regulated by phosphoinositide 3-kinase (PI3K) activation of Rac-Pak signaling. Furthermore, inhibition of Rac-dependent macropinocytosis blocks glucose-independent proliferation. We find that degradation of internalized protein produces amino acids, including alanine, which generates TCA cycle and glycolytic intermediates in the absence of glucose. In this process, the conversion of alanine to pyruvate by alanine transaminase 2 (ALT2) is critical for survival during glucose starvation. Collectively, Rac driven macropinocytosis of extracellular protein is an adaptive metabolic pathway used by a subset of lung cancers to survive states of glucose deprivation, and may serve as a potential drug target for cancer therapy. |
DOI | 10.3390/cancers11010037 |
Alternate Journal | Cancers (Basel) |
PubMed ID | 30609754 |
PubMed Central ID | PMC6356657 |
Grant List | PF-17-001-01-TBE / / American Cancer Society / T32 AI007640 / AI / NIAID NIH HHS / United States P01 CA117969 / CA / NCI NIH HHS / United States P01 CA120964 / CA / NCI NIH HHS / United States R35 CA197588 / CA / NCI NIH HHS / United States CA120964, R35CA197588 / CA / NCI NIH HHS / United States |