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Publications

Journal Article Epublish

PubMed: 42653152 DOI: 10.3390/ijms27167147

Catalase Defines Radiotherapy Resistance and a Therapeutic Vulnerability in Rhabdomyosarcoma.

Int J Mol Sci 27(16)

Authors: Silvia Codenotti, Francesco Marampon, Francesca Megiorni, Enrico Romano, Silvia Pomella, Rossella Rota, Isabella Zanella, Eugenia Quiros-Roldan, Giovanni Corsetti, Luca Triggiani, Sara Salucci, Irene Faenza, Martina Benedetti, Mattia Bugatti, William Vermi, Alessandro Fanzani

Affiliations

  • Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
  • Unit of Pathology, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy.
  • Department of Well-being, Health and Environmental Sustainability, Sapienza University of Rome, Via delle Fontanelle s.n.c. 02100 Rieti, Italy.
  • Department of Sense Organs, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165 Rome, Italy.
  • Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
  • Medical Genetics Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy.
  • Division of Infectious and Tropical Diseases, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy.
  • Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
  • Radiation Oncology, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy.
  • Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Via Luigi Zamboni 33, 40126 Bologna, Italy.

Abstract

Therapeutic resistance remains a critical obstacle in rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma. Increasing evidence implicates redox adaptation in tumor survival and treatment failure. Here, we investigated the functional role and clinical relevance of catalase, a primary hydrogen peroxide-detoxifying enzyme, in modulating RMS therapeutic response. Integrated transcriptomic analyses revealed that while catalase is overall downregulated in RMS compared to healthy skeletal muscle, elevated expression strongly correlates with high-risk, metastatic disease and poor overall survival. In human RMS cell lines, catalase was detectable, and its pharmacological inhibition using 3-amino-1,2,4-triazole (3-ATA) promoted reactive oxygen species (ROS) accumulation, sensitizing cells to standard chemotherapeutics. Notably, robust catalase upregulation was observed in RMS cell models characterized by intrinsic and acquired radioresistance, with strong immunoreactivity validated on cell-block sections. Immunohistochemical validation across patient specimens revealed generally weak catalase expression in RMS tumors, whereas strong reactivity was observed in a secondary embryonal RMS (ERMS) arisen following chemoradiotherapy for nasopharyngeal carcinoma. Functionally, targeting catalase with 3-ATA restored both radio- and chemosensitivity in radioresistant RMS lines. Furthermore, co-targeting catalase and Akt using sub-toxic doses of 3-ATA and MK-2206 cooperatively enhanced oxidative stress-mediated cytotoxicity in resistant cells. Together, these findings identify catalase as a pivotal driver of adaptive radioresistance and establish dual catalase/Akt targeting as a promising pro-oxidant strategy to overcome radiotherapy resistance in RMS.

MeSH

Radiotherapy, Cells, Rhabdomyosarcoma, Neoplasms, Sarcoma, Catalase, Therapeutics