Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells

• Published in: Cellular and molecular life sciences : CMLS 2021-03, Vol.78 (6), p.3021-3044
• Main Authors: Chen, Oleg, Manig, Friederike, Lehmann, Loreen, Sorour, Nagwa, Löck, Steffen, Yu, Zhanru, Dubrovska, Anna, Baumann, Michael, Kessler, Benedikt M., Stasyk, Oleh, Kunz-Schughart, Leoni A.
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4 - antagonists & inhibitors; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Apoptosis; Apoptosis - drug effects; Arginine; Arginine - deficiency; Arginine - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Canavanine; Canavanine - pharmacology; Cancer; Cell Biology; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular stress response; Culture Media - chemistry; Deprivation; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - antagonists & inhibitors; Endoribonucleases - genetics; Endoribonucleases - metabolism; Eukaryotic Initiation Factor-2 - genetics; Eukaryotic Initiation Factor-2 - metabolism; GADD34 protein; Head & neck cancer; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; Irradiation; Life Sciences; Membrane proteins; Metabolism; Molecular modelling; Original; Original Article; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Radiation; Radiation Tolerance - drug effects; Radiosensitivity; Radiosensitization; RNA Interference; RNA, Small Interfering - metabolism; Sensitivity; Signal Transduction - drug effects; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; Transcription Factor CHOP - antagonists & inhibitors; Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism; X-Rays
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-020-03704-7

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.