Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer Journal Article
| Authors: | Wahi, K.; Freidman, N.; Wang, Q.; Devadason, M.; Quek, L. E.; Pang, A.; Lloyd, L.; Larance, M.; Zanini, F.; Harvey, K.; O’Toole, S.; Guan, Y. F.; Holst, J. |
| Article Title: | Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer |
| Abstract: | Triple-negative breast cancer (TNBC) metabolism and cell growth uniquely rely on glutamine uptake by the transporter ASCT2. Despite previous data reporting cell growth inhibition after ASCT2 knockdown, we here show that ASCT2 CRISPR knockout is tolerated by TNBC cell lines. Despite the loss of a glutamine transporter and low rate of glutamine uptake, intracellular glutamine steady-state levels were increased in ASCT2 knockout compared to control cells. Proteomics analysis revealed upregulation of macropinocytosis, reduction in glutamine efflux and increased glutamine synthesis in ASCT2 knockout cells. Deletion of ASCT2 in the TNBC cell line HCC1806 induced a strong increase in macropinocytosis across five ASCT2 knockout clones, compared to a modest increase in ASCT2 knockdown. In contrast, ASCT2 knockout impaired cell proliferation in the non-macropinocytic HCC1569 breast cancer cells. These data identify macropinocytosis as a critical secondary glutamine acquisition pathway in TNBC and a novel resistance mechanism to strategies targeting glutamine uptake alone. Despite this adaptation, TNBC cells continue to rely on glutamine metabolism for their growth, providing a rationale for targeting of more downstream glutamine metabolism components. © The Author(s) 2024. |
| Keywords: | controlled study; protein expression; genetics; flow cytometry; cell proliferation; mass spectrometry; phenotype; metabolism; cell viability; cell survival; cell cycle; gene overexpression; apoptosis; gene expression; cell growth; tumor volume; cohort analysis; tumor xenograft; pathology; cell line, tumor; proteomics; genetic transfection; protein synthesis; tumor cell line; western blotting; cancer stem cell; immunoblotting; upregulation; oxidative stress; oxygen consumption; fluorescence activated cell sorting; glucose intake; glucose transport; glycolysis; glutamine; virus transmission; growth inhibition; endosome; minor histocompatibility antigens; cell cloning; citric acid cycle; mitochondrial respiration; colony formation; triple negative breast cancer; metabolomics; triple-negative breast cancer; minor histocompatibility antigen; liquid chromatography-mass spectrometry; pentose phosphate cycle; macropinocytosis; pinocytosis; ferroptosis; humans; human; female; article; ultra performance liquid chromatography; amino acid transporter; asct2; amino acid transport system asc; live cell imaging; crispr cas system; triple negative breast neoplasms; glutamine metabolism; photon correlation spectroscopy; mda-mb-231 cell line; mda-mb-468 cell line; fusion regulatory protein 1, heavy chain; cd98 antigen; slc3a2 protein, human |
| Journal Title: | EMBO Journal |
| Volume: | 43 |
| Issue: | 23 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2024-12-02 |
| Start Page: | 5857 |
| End Page: | 5882 |
| Language: | English |
| DOI: | 10.1038/s44318-024-00271-6 |
| PUBMED: | 39420093 |
| PROVIDER: | scopus |
| PMCID: | PMC11611898 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
