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Updated: Jan 22, 2026

Activating Autophagy by Aerobic Exercise in Mice
Published on: February 3, 2017
SLC3A2/CD98hc, autophagy and tumor radioresistance: a link confirmed
David Digomann1, Annett Linge1,2,3,4,5,6, Anna Dubrovska1,2,3,7
1OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf , Dresden , Germany.
Abstract:
SLC3A2/CD98hc (solute carrier family 3 member 2) and its light chain subunits constitute the heterodimeric transmembrane complexes that mediate amino acid transport and regulate MTOR and macroautophagy/autophagy. Despite the proven tumorigenic role of SLC3A2 in a number of cancers including head and neck squamous cell carcinomas (HNSCC), the link between SLC3A2, autophagy regulation and tumor radioresistance remained elusive. In a recently published study we demonstrated that low levels of SLC3A2 and SLC7A5/LAT1 protein expression significantly correlate with good clinical prognosis in locally advanced HNSCC treated with primary radiochemotherapy. The SLC3A2-deficient HNSCC cells show a higher radiosensitivity and increased autophagy levels. We found that autophagy activation is a tumor survival strategy to overcome nutrient stress by lack of SLC3A2 and to withstand radiation-mediated cell damage. Inhibition of the autophagy activation in SLC3A2 knockout HNSCC cells by knockdown of ATG5 expression or treatment with bafilomycin A1 results in radiosensitivity. Consequently, the expression levels of ATG5 correlates with overall survival in HNSCC patients, and autophagy inhibition in combination with SLC3A2-targeted therapy can be a promising strategy for HNSCC radiosensitization. Abbreviations: CD98hc: CD98 heavy chain CSC cancer stem cells; EAA: essential amino acids; GSH: glutathione; MTOR: mammalian target of rapamycin; HNSCC: head and neck squamous cell carcinoma; RCTx: primary radiochemotherapy; PORT-C: postoperative radiochemotherapy; ROS: reactive oxygen species; SLC3A2: solute carrier family 3 member 2; TCA cycle: tricarboxylic acid cycle.
Insights
Low SLC3A2 expression in head and neck cancers enhances autophagy, increasing tumor radioresistance. Inhibiting autophagy alongside SLC3A2-targeted therapy may improve HNSCC radiosensitization.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- SLC3A2/CD98hc is implicated in amino acid transport, mTOR signaling, and autophagy.
- SLC3A2 has a known tumorigenic role in various cancers, including head and neck squamous cell carcinomas (HNSCC).
- The interplay between SLC3A2, autophagy, and radioresistance in HNSCC was previously unclear.
Purpose of the Study:
- To investigate the role of SLC3A2 in HNSCC radioresistance.
- To explore the relationship between SLC3A2 expression, autophagy, and patient prognosis.
- To evaluate SLC3A2 and autophagy inhibition as a potential radiosensitization strategy for HNSCC.
Main Methods:
- Analysis of SLC3A2 and SLC7A5/LAT1 protein expression in HNSCC patients treated with radiochemotherapy.
- Assessment of radiosensitivity and autophagy levels in SLC3A2-deficient HNSCC cells.
- Inhibition of autophagy in SLC3A2 knockout cells using ATG5 knockdown or bafilomycin A1 treatment.
Main Results:
- Low SLC3A2 and SLC7A5/LAT1 expression correlated with favorable prognosis in locally advanced HNSCC.
- SLC3A2-deficient HNSCC cells exhibited increased radiosensitivity and heightened autophagy.
- Autophagy activation serves as a survival mechanism against nutrient stress and radiation damage.
- Autophagy inhibition (ATG5 knockdown, bafilomycin A1) sensitized SLC3A2-deficient cells to radiation.
- ATG5 expression levels correlated with overall survival in HNSCC patients.
Conclusions:
- SLC3A2 deficiency in HNSCC leads to increased autophagy and radiosensitivity.
- Autophagy acts as a survival mechanism in HNSCC under nutrient stress and radiation.
- Combined SLC3A2-targeted therapy and autophagy inhibition presents a promising strategy for HNSCC radiosensitization.
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