ATG12 deficiency results in intracellular glutamine depletion, abrogation of tumor hypoxia and a favorable prognosis in cancer
Open accessAbstract
Hypoxia is a common feature of solid tumors and is associated with increased tumor progression, resistance to therapy and increased metastasis. Hence, tumor hypoxia is a prognostic factor independent of treatment modality. To survive hypoxia, cells activate macroautophagy/autophagy. Paradoxically, in several cancer types, mutations or loss of essential autophagy genes have been reported that are associated with earlier onset of tumor growth. However, to our knowledge, the phenotypic and therapeutic consequences of autophagy deficiency have remained unexplored. In this study, we determined autophagy-defects in head and neck squamous cell carcinoma (HNSCC) and observed that expression of ATG12 (autophagy related 12) was lost in 25%-40% of HNSCC. In line, ATG12 loss is associated with absence of hypoxia, as determined by pimonidazole immunohistochemistry. Hence, ATG12 loss is associated with improved prognosis after therapy in two independent HNSCC cohorts and 7 additional cancer types. In vivo, ATG12 targeting resulted in decreased hypoxia tolerance, increased necrosis and sensitivity of the tumor to therapy, but in vitro ATG12-deficient cells displayed enhanced survival in nutrient-rich culture medium. Besides oxygen, delivery of glucose was hampered in hypoxic regions in vivo, which increases the reliance of cells on other carbon sources (e.g., L-glutamine). We observed decreased intracellular L-glutamine levels in ATG12-deficient cells during hypoxia and increased cell killing after L-glutamine depletion, indicating a central role for ATG12 in maintaining L-glutamine homeostasis. Our results demonstrate that ATG12low tumors represent a phenotypically different subtype that, due to the lowered hypoxia tolerance, display a favorable outcome after therapy.Abbreviations: ARCON:accelerated radiotherapy with carbogen and nicotinamide; ATG: autophagy related; BrdUrd: bromodeoxyuridine; CA9/CAIX: carbonic anhydrase 9; HIF1A/HIF1α: hypoxia inducible factor 1 subunit alpha; HNSCC: head and neck squamous cell carcinoma; HPV: human papilloma virus; HR: hazard ratio; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; mRNA: messenger ribonucleic acid; PCR: polymerase chain reaction; SLC2A1/GLUT1: solute carrier family 2 member 1; TCGA: the Cancer Genome Atlas; TME: tumor microenvironment; UTR: untranslated region; VEGF: vascular endothelial growth factor
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ATG12 plays an essential role in maintaining L-glutamine homeostasis.
“This suggests that ATG12 plays an essential role in maintaining L‐glutamine homeostasis.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [57]
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Hypoxia signaling in cancer: Implications for therapeutic interventions
Zhuang, Y., Liu, K., He, Q., Gu, X., Jiang, C., & Wu, J. (2023) · MedComm · doi:10.1002/mco2.203 · Cited by 119 · see citing works
- Authors
- Keulers, T. G., Koch, A., van Gisbergen, M. W., Barbeau, L. M. O., Zonneveld, M. I., de Jong, M. C., Savelkouls, K. G. M., Wanders, R. G., Bussink, J., Melotte, V., & Rouschop, K. M. A.
- Affiliations
- Maastricht University Medical Centre (NL)
- Maastricht University
- The Netherlands Cancer Institute
- Maastricht University (NL)
- Radboud University Medical Center (NL)
- Corresponding author
- Rouschop, Kasper M.A.
- ORCID
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2021-12-14
- Volume
- 18
- Issue
- 8
- Pages
- 1898-1914
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC9450974
- OpenAlex
- W4200362343
- Cited by
- 30
- References
- 58
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 5
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Autophagy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Dutch Cancer Society (UM 2012-5506)
- worldwide cancer research (16-0265)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- ATG12, autophagy dysfunction, tumor hypoxia, head and neck squamous cell carcinoma, prognostic factors, tumor necrosis, hypoxia tolerance, autophagy-related genes, carbonic anhydrase IX, HIF1A, LC3B, pimonidazole
- MeSH terms
- Autophagy-Related Protein 12, Tumor Hypoxia, Squamous Cell Carcinoma of Head and Neck, Animals, Autophagy, Fibroblasts, Glutamine, Head and Neck Neoplasms, Humans, Vascular Endothelial Growth Factor A, Mice, Tumor Microenvironment
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