Differential transcriptome response to proton versus X-ray radiation reveals novel candidate targets for combinatorial PT therapy in lymphoma

Abstract

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Cellular plasticity upon proton irradiation determines tumor cell radiosensitivity

“…The obtained results indicated that, besides stemness, the repair of proton-induced complex DNA DSBs is a key determinant of intracellular sensitivity. We also observed a higher amount of residual ɣH2AX foci indicative of unrepaired DNA DSBs after proton irradiation in comparison with photons, which supports the notion that proton irradiation results in more complex DNA damages, especially at regions with a higher LET (Carter et al, 2018;Cuaron et al, 2016;Fu et al, 2012;Hojo et al, 2017;Oeck et al, 2018;Sertorio et al, 2020;Vitti and Parsons, 2019). Besides direct DNA damages, high intracellular ROS levels contribute to indirect DNA damages and other cytotoxic effects.…”

“…To summarize, proton irradiation significantly reduces the clonogenic survival of PCa and GBM but not HNSCC cell lines in comparison with photons. Our results support the body of literature indicating the induction of more complex DNA damages and delayed repair as one of the underlying mechanisms (Carter et al, 2018;Cuaron et al, 2016;Fu et al, 2012;Hojo et al, 2017;Oeck et al, 2018;Sertorio et al, 2020;Vitti and Parsons, 2019). However, we found no increase in oxidative stress following proton irradiation in comparison with photons.…”

“…We found alterations in NF-kB signaling, senescence, and autophagy as well as interferon response determined by the key regulatory genes ATF3, GDF15, and BIRC3. Other groups reported an altered gene expression 4 to 12 h after proton irradiation with upregulated DNA repair, unfolded protein response and cell-cycle arrest (Ha et al, 2015;Narang et al, 2015;Sertorio et al, 2020). Similar findings were reported on the phospho-proteome level in 3D pancreatic tumoroid cultures, which displayed alterations in core components of the DNA repair system, such as ataxia telangiectasia mutated and checkpoint kinase 1/2 (Chk1/2) after proton irradiation (Go ¨rte et al, 2020).…”

“…Besides direct DNA damages, high intracellular ROS levels contribute to indirect DNA damages and other cytotoxic effects. ROS levels have been described to be higher after proton than photon irradiation in lymphoma cell lines (Sertorio et al, 2020) as well as in stem-like populations of GBM and NSCLC (Alan Mitteer et al, 2015;Zhang et al, 2013). On the contrary, we found reduced ROS production in GBM cells and decreased GSH levels in PCa cells after proton irradiation in comparison with photons.…”

Comparison of the Medical Uses and Cellular Effects of High and Low Linear Energy Transfer Radiation

“…Many primary cells have been shown to primarily undergo accelerated senescence from low-LET radiation, but apoptosis can be observed at higher total doses of low-LET radiation (>50 Gy) [ 127 , 136 ]. Studies of cancer and normal cells have provided evidence that the biological “decisions” for non-survival versus survival are guided by signaling pathways, activated downstream of the initial DNA damage response, that are influenced by numerous characteristics specific to each cell type and its environment [ 114 , 123 , 133 , 135 , 136 , 138 , 139 , 140 , 141 ].…”