Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy.
|Number of pages||24|
|Journal||Cellular and Molecular Life Sciences|
|Publication status||Published - Mar 2021|
Sustainable Development Goals
- Activating Transcription Factor 4/antagonists & inhibitors, Apoptosis/drug effects, Arginine/deficiency, Canavanine/pharmacology, Cell Culture Techniques, Cell Line, Tumor, Cell Proliferation/drug effects, Culture Media/chemistry, Endoplasmic Reticulum Stress/drug effects, Endoribonucleases/antagonists & inhibitors, Eukaryotic Initiation Factor-2/genetics, Head and Neck Neoplasms/metabolism, Humans, Protein Serine-Threonine Kinases/antagonists & inhibitors, RNA Interference, RNA, Small Interfering/metabolism, Radiation Tolerance/drug effects, Signal Transduction/drug effects, Squamous Cell Carcinoma of Head and Neck/metabolism, Transcription Factor CHOP/antagonists & inhibitors, X-Rays