Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy

Abstract

Currently, cancer treatment mainly consists of surgery, radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy, of which radiotherapy is one of the major pillars. However, the occurrence of radioresistance largely limits its therapeutic effect. Metabolic reprogramming is an important hallmark in cancer progression and treatment resistance. In radiotherapy, DNA breakage is the major mechanism of cell damage, and in turn, cancer cells are prone to increase the metabolic flux of glucose, glutamine, serine, arginine, fatty acids etc., thus providing sufficient substrates and energy for DNA damage repair. Therefore, studying the linkage between metabolic reprogramming and cancer radioresistance may provide new ideas for improving the efficacy of tumor therapy. This review mainly focuses on the role of metabolic alterations, including glucose, amino acid, lipid, nucleotide and other ion metabolism, in radioresistance, and proposes possible therapeutic targets to improve the efficacy of cancer radiotherapy.

Proteomic and metabolomic signatures of rectal tumor discriminate patients with different responses to preoperative radiotherapy

“…Interestingly, different groups of cells present in the tumor may have various nutrient uptake from TME, with glucose being preferentially delivered to immune cells while glutamine and fatty acids are primarily distributed to cancer cells ( 28 ). As a result, targeting a single metabolite alone is insufficient to overcome radioresistance because tumor cells and other cells in the TME (including immune system cells) exhibit metabolic heterogeneity ( 29 ). Moreover, although the analysis of clinical data revealed statistically significant differences between groups of PR and GR with respect to radiation dose delivered during neo-RT (the contribution of radiation schemes involving higher doses was higher in the GR’ group), radiation dose was barely associated with the abundance of differentiating proteins and metabolites (particularly when the correlations with radiation dose were analyzed in each group separately).…”

“…Furthermore, cancer cells may develop radioresistance via reprogramming of lipid metabolism. We detected in PR elevated levels of enzymes (COX-2, ACSS2, FDPS, FASN, ACAT2, ACLY, SLC12A2) and metabolites (arachidonic acid and carnitine) involved in lipid metabolism, which have been linked to radioresistance of cancer cells ( 29 ). The major mechanism that enables the development of tumor radioresistance is DNA damage repair, which needs a significant nucleotide accumulation.…”

“…On the other hand, enzymes involved in the de novo nucleotide synthesis pathway (e.g. IMPDH) have emerged as targets for radiosensitization ( 29 ). Here we detected in PR elevated levels of inosine monophosphate dehydrogenase, while the abundance of inosine was reduced.…”

Editorial: Targeting nucleotide metabolism for enhancing antitumor immunity

“…A single metabolic target is not enough to overcome tumor cell radioresistance due to metabolic heterogeneity. According to Yu et al., related nucleotide synthesis enzymes (such as TS/PPAT/IMPDH) have been shown to be radiation sensitizing ( 25 ).…”

Estudo da ação antitumoral de nanopartículas de prata biogênicas

“…YU, 2021). No caso de radioterapia, as células podem ativar vias de reparo de danos no DNA, aumentar a expressão de proteínas anti-apoptóticas e induzir autofagia para sobreviver a espécie reativa de oxigênio (ROS) causado pela radiação (YU et al, 2023).…”