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The authors would like to thank all patients who were willing to donate their samples, without their support this work would not be possible. We thank Isabel Sastre for her technical support. This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-70561-R; MINECO/FEDER, EU); the Autonomous Community of Madrid, Spain (B2017/BMD-3778; LINFOMAS-CM) and the Spanish Association Against Cancer (AECC, 2018; PROYE18054PIRI). Institutional grants from the Fundacion Ramon Areces and Banco de Santander are also acknowledged. The Spanish Ministry and the Juan de la Cierva fellowship program must be acknowledged for I.G.V. contract (IJCI-2016-29155).

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Differential molecular response in mice and human thymocytes exposed to a combined-dose radiation regime

Publicado en:Scientific Reports. 12 (1): - 2022-01-01 12(1), DOI: 10.1038/s41598-022-07166-8

Autores: Lopez-Nieva, Pilar; Gonzalez-Vasconcellos, Iria; Gonzalez-Sanchez, Laura; Cobos-Fernandez, Maria A.; Ruiz-Garcia, Sara; Sanchez Perez, Raul; Aroca, Angel; Fernandez-Piqueras, Jose; Santos, Javier;

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In the quest for more effective radiation treatment options that can improve both cell killing and healthy tissue recovery, combined radiation therapies are lately in the spotlight. The molecular response to a combined radiation regime where exposure to an initial low dose (priming dose) of ionizing radiation is administered prior to a subsequent higher radiation dose (challenging dose) after a given latency period have not been thoroughly explored. In this study we report on the differential response to either a combined radiation regime or a single challenging dose both in mouse in vivo and in human ex vivo thymocytes. A differential cell cycle response including an increase in the subG1 fraction on cells exposed to the combined regime was found. Together with this, a differential protein expression profiling in several pathways including cell cycle control (ATM, TP53, p21(CDKN1A)), damage response (gamma H2AX) and cell death pathways such as apoptosis (Cleaved Caspase-3, PARP1, PKC delta and H3T45ph) and ferroptosis (xCT/GPX4) was demonstrated. This study also shows the epigenetic regulation following a combined regime that alters the expression of chromatin modifiers such as DNMTs (DNMT1, DNMT2, DNMT3A, DNMT3B, DNMT3L) and glycosylases (MBD4 and TDG). Furthermore, a study of the underlying cellular status six hours after the priming dose alone showed evidence of retained modifications on the molecular and epigenetic pathways suggesting that the priming dose infers a "radiation awareness phenotype" to the thymocytes, a sensitization key to the differential response seen after the second hit with the challenging dose. These data suggest that combined-dose radiation regimes could be more efficient at making cells respond to radiation and it would be interesting to further investigate how can these schemes be of use to potential new radiation therapies.

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