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Cancers (Basel). 2019 Jan 2;11(1). pii: E37. doi: 10.3390/cancers11010037.

Rac-Mediated Macropinocytosis of Extracellular Protein Promotes Glucose Independence in Non-Small Cell Lung Cancer.

Author information

1
Meyer Cancer Center, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10021, USA. cih2002@med.cornell.edu.
2
Meyer Cancer Center, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10021, USA. beh2020@med.cornell.edu.
3
Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021, USA. guz2004@med.cornell.edu.
4
Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021, USA. tas2033@med.cornell.edu.
5
Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021, USA. zhe.cheng@nyu.edu.
6
Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medicine, 1300 York Ave A-421, New York, NY 10065, USA. roxanne.morris22@gmail.com.
7
Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medicine, 1300 York Ave A-421, New York, NY 10065, USA. kyr9001@med.cornell.edu.
8
Meyer Cancer Center, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10021, USA. mdg9010@med.cornell.edu.
9
Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. mdg9010@med.cornell.edu.
10
Meyer Cancer Center, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10021, USA. LCantley@med.cornell.edu.

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.

KEYWORDS:

Rac; glucose; macropinocytosis; metabolism

PMID:
30609754
DOI:
10.3390/cancers11010037
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