Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells
Abstract
ATP plays central roles in cancer metabolism and the Warburg effect. Intratumoral ATP concentrations are up to 10(4) times higher than those of interstitial ATP in normal tissues. However, extracellular ATP is not known to enter cancer cells. Here we report that human A549 lung cancer cells internalized extracellular ATP by macropinocytosis as demonstrated by colocalization of a nonhydrolyzable fluorescent ATP and a macropinocytosis tracer high-molecular-weight dextran, as well as by a macropinocytosis inhibitor study. Extracellular ATP also induced increase of intracellular ATP levels, without involving transcription and translation at significant levels, and cancer cells' resistance to ATP-competitor anticancer drugs, likely through the mechanism of ATP internalization. These findings, described for the first time, have profound implications in ATP-sharing among cancer cells in tumors and highlight a novel anticancer target.
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Macropinocytosis has been implicated in resistance to tyrosine kinase inhibitors and standard-of-care agents such as gemcitabine and 5-FU.
“Macropinocytosis has also been implicated in resistance to tyrosine kinase inhibitors and standard-of-care agents, such as gemcitabine and 5-fluorouracil (5-FU).34,35”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [34]
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Emran, T. B., Shahriar, A., Mahmud, A. R., Rahman, T., Abir, M. H., Siddiquee, M. F. R., Ahmed, H., Rahman, N., Nainu, F., Wahyudin, E., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.891652 · Cited by 606 · see citing works
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“34,35 Together, these findings suggest that SDC1-mediated macropinocytosis may represent a general mechanism underlying therapy resistance.”
Self-citation
- Authors
- Qian, Y., Wang, X., Liu, Y., Li, Y., Colvin, R. A., Tong, L., Wu, S., & Chen, X.
- Affiliations
- Ohio University (US)
- ORCID
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 351
- Issue
- 2
- Pages
- 242-251
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2006873065
- Cited by
- 149
- References
- 5
- Citations by year
- 2026: 17 · 2025: 11 · 2024: 8 · 2023: 12 · 2022: 19 · 2021: 26 · 2020: 16 · 2019: 9 · 2018: 7 · 2017: 9 · 2016: 6 · 2015: 7 · 2014: 2
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- extracellular ATP, macropinocytosis, drug resistance, lung cancer cells, Warburg effect, cancer metabolism
- MeSH terms
- Adenosine Triphosphate, Adenylate Kinase, Antineoplastic Agents, Dose-Response Relationship, Drug, Extracellular Space, Glycolysis, Humans, Lung Neoplasms, Oxidative Phosphorylation, Phosphorylation, Pinocytosis, Protein-Tyrosine Kinases, Drug Resistance, Neoplasm, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Growth Processes
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