Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Dual role of ER stress in response to metabolic co‑targeting and radiosensitivity in head and neck cancer cells Oleg Chen1,2 · Friederike Manig1,3 · Loreen Lehmann1 · Nagwa Sorour1 · Steffen Löck1,4,5,6 · Zhanru Yu7 · Anna Dubrovska1,4,5,8 · Michael Baumann1,5 · Benedikt M. Kessler7 · Oleh Stasyk2 · Leoni A. Kunz‑Schughart1,9 Received: 25 May 2020 / Revised: 19 October 2020 / Accepted: 4 November 2020 © The Author(s) 2020
Abstract 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. Keywords Metabolic targeting · Arginine-deprivation therapy · ER stress · Canavanine · Radiosensitization · Head and neck squamous carcinoma · 3-D culture Abbreviations ADT Arginine deprivation therapy Akt Protein kinase B Arg Arginine ASS Argininosuccinate synthetase ATF3 Activating transcription factor 3 ATF4 Activating transcription factor 4 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03704-7) contains supplementary material, which is available to authorized users. * Leoni A. Kunz‑Schughart leoni.kunz‑[email protected] 1
OncoRay, National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Fetscherstraße 74, 01307 Dresden, Germany
2
Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine
3
Chair of Food Chemistry, TU Dresden, Dresden, Germany
4
German Cancer Consortium (DKTK), Partner Site Dresden, Germany
ATF6 Activating transcription factor 6 Atg12 Autophagy related 12 Bax Bcl-2-associated X protein Bcl-2 B-cell lymphoma 2 Bim Bcl-2-like protein 11 Cav Canavanine CHOP C/EBP homologous protein Cit Citrulline comb-ADT Arginine deprivation therapy combined with canavanine 5
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