Journal Article

DKFZ-2025-01313

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Adaptation to Arginine Deprivation Leads to a More Aggressive, Therapy-Resistant Phenotype in HNSCC Cells.

Chen, O. ; Vovk, O. ; Polishchuk, N. ; Mayevska, O. ; Shuvayeva, G. ; Demir, M. ; Lukiyanchuk, V. ; Kunz-Schughart, L. A. ; Dubrovska, A.DKFZ* ; Stasyk, O.

2025
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/biom15060900

Abstract: Purpose: The development of acquired resistance to arginine deprivation therapy (ADT) is a major barrier to its efficacy. This study aimed to elucidate the possible mechanisms underlying the resistance to ADT. Methods: We applied repeated ADT and established a subline SAS-R9 of the human head and neck squamous cell carcinoma (HNSCC) cells semi-resistant to arginine (Arg) deprivation in vitro. This subline was compared to the parental SAS cell lines for its relative clonogenic proliferation, aggregation, adhesion, and migration capacities. The transcriptomic changes were assessed by RNA sequencing. Signaling pathway alterations were confirmed by RT-PCR and Western blotting. Relative cell radioresistance was analyzed by radiobiological clonogenic survival assay. DNA double-strand break (DSB) repair was assessed by γH2A.X foci analysis. Results: SAS-R9 cells showed higher survival in response to ADT and radiotherapy, elevated clonogenic proliferation rate, cell-cell aggregation, and cell-matrix adhesion, along with increased epithelial-mesenchymal transition (EMT) markers and enhanced DNA DSB repair, potentially related to a more aggressive and therapy-resistant phenotype. Conclusions: While acute ADT has radiosensitizing potential, this new study suggests that long-term, repeated ADT is associated with cell selection and reprogramming, resulting in resistance to radiotherapy-induced DNA damage and higher tumor cell aggressiveness.

Keyword(s): Humans (MeSH) ; Arginine: deficiency (MeSH) ; Arginine: metabolism (MeSH) ; Squamous Cell Carcinoma of Head and Neck: metabolism (MeSH) ; Squamous Cell Carcinoma of Head and Neck: pathology (MeSH) ; Squamous Cell Carcinoma of Head and Neck: genetics (MeSH) ; Cell Line, Tumor (MeSH) ; Head and Neck Neoplasms: metabolism (MeSH) ; Head and Neck Neoplasms: pathology (MeSH) ; Head and Neck Neoplasms: genetics (MeSH) ; Epithelial-Mesenchymal Transition: drug effects (MeSH) ; Cell Proliferation: drug effects (MeSH) ; Radiation Tolerance (MeSH) ; Phenotype (MeSH) ; Drug Resistance, Neoplasm (MeSH) ; Cell Movement (MeSH) ; DNA Repair (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; DNA Breaks, Double-Stranded (MeSH) ; Cell Adhesion (MeSH) ; Cell Survival: drug effects (MeSH) ; DNA repair ; acquired drug resistance ; arginine deprivation therapy ; epithelial–mesenchymal transition ; head and neck squamous cell carcinoma ; radiosensitization ; recombinant human arginase type 1 ; Arginine

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Dresden (DD01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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