Abstract
BackgroundRecent studies have emphasised the important role of amino acids in cancer metabolism. Cold physical plasma is an evolving technology employed to target tumour cells by introducing reactive oxygen species (ROS). However, limited understanding is available on the role of metabolic reprogramming in tumour cells fostering or reducing plasma-induced cancer cell death.MethodsThe utilisation and impact of major metabolic substrates of fatty acid, amino acid and TCA pathways were investigated in several tumour cell lines following plasma exposure by qPCR, immunoblotting and cell death analysis.ResultsMetabolic substrates were utilised in Panc-1 and HeLa but not in OVCAR3 and SK-MEL-28 cells following plasma treatment. Among the key genes governing these pathways, ASCT2 and SLC3A2 were consistently upregulated in Panc-1, Miapaca2GR, HeLa and MeWo cells. siRNA-mediated knockdown of ASCT2, glutamine depletion and pharmacological inhibition with V9302 sensitised HeLa cells to the plasma-induced cell death. Exogenous supplementation of glutamine, valine or tyrosine led to improved metabolism and viability of tumour cells following plasma treatment.ConclusionThese data suggest the amino acid influx driving metabolic reprogramming in tumour cells exposed to physical plasma, governing the extent of cell death. This pathway could be targeted in combination with existing anti-tumour agents.
Highlights
Recent studies have emphasised the important role of amino acids in cancer metabolism
The resazurin-based quantification of metabolic activity 24 h after plasma treatment revealed that Panc-1 and HeLa had a higher survival fraction compared to SK-MEL-28 and OVCAR3 cells (Fig. S1B)
Glutamine-deprived culture media sensitised both MeWo (Fig. S2A) and Panc-1 (Fig. S2B) cells to plasma treatment. These results indicated that some tumour cell lines depended on ASCT2 expression and glutamine metabolism to protect themselves from the toxic consequences of plasma-derived reactive oxygen species (ROS)
Summary
Recent studies have emphasised the important role of amino acids in cancer metabolism. Cold physical plasma is an evolving technology employed to target tumour cells by introducing reactive oxygen species (ROS). CONCLUSION: These data suggest the amino acid influx driving metabolic reprogramming in tumour cells exposed to physical plasma, governing the extent of cell death. This pathway could be targeted in combination with existing anti-tumour agents. A particular trait of many types of cancers is their ability to evolve and become refractory to different treatment modalities, such as chemotherapy, radiotherapy and immunotherapy To this end, novel treatment avenues are utterly needed to target tumours from multiple pathways simultaneously. Because of increased metabolic activity, tumour cells accumulate ROS, leading to increased oxidative stress.[14,15] To cope with the oxidative stress, tumour cells adapt several ROS scavenging systems to maintain ROS levels below the toxic threshold to prevent oxidative damage.[16]
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