ATO Increases ROS Production and Apoptosis of Cells by Enhancing Calpain-Mediated Degradation of the Cancer Survival Protein TG2

• Published in: International journal of molecular sciences Vol. 24; no. 13; p. 10938
• Main Authors: Jambrovics, Károly, Póliska, Szilárd, Scholtz, Beáta, Uray, Iván P, Balajthy, Zoltán
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.06.2023; MDPI
• Subjects: Angiogenesis; Antioxidants; APL; Apoptosis; Arsenic; Arsenic trioxide; Arsenic Trioxide - pharmacology; Arsenic Trioxide - therapeutic use; Arsenicals - pharmacology; ATO; Breast cancer; Calpain; Calpain - pharmacology; Cancer; Cancer therapies; Care and treatment; Cell death; Cell differentiation; cell survival; Cells; Cellular signal transduction; Cellular stress response; Chemotherapy; Cytotoxicity; Drug resistance; Enzymes; Epigenetic inheritance; Epigenetics; Epithelial cells; Epithelium; Genes; Genotoxicity; Humans; Kinases; Leukemia; Leukemia, Promyelocytic, Acute - metabolism; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Medical prognosis; Metastases; Oxidative stress; Oxides - pharmacology; Peripheral blood mononuclear cells; Physiology; Protein expression; Protein Glutamine gamma Glutamyltransferase 2; Proteins; Proteolysis; reactive oxygen species; Reactive Oxygen Species - pharmacology; Retinoic acid; Signal transduction; Statistics; Stem cells; Survival; Survival factor; Transcription factors; Transglutaminase 2; Tretinoin; Tretinoin - pharmacology; cell survival; cell death; reactive oxygen species; cancer; ATO; APL; TG2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241310938

Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signalling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial-mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukaemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.