The amino acid metabolism is essential for evading physical plasma-induced tumour cell death

Abstract

Background 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). However, limited understanding is available on the role of metabolic reprogramming in tumour cells fostering or reducing plasma-induced cancer cell death. Methods The 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. Results Metabolic 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. 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.

Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence

“…A recent study showed that ovarian cancer cells post ROS exposure did not show any significant alterations in the overall consumption of metabolic substrates across different metabolic pathways. The consumption of metabolic substrates remained more or less similar to that of the cells that were not exposed to ROS [283]. This proves that identifying a proper therapeutic agent that effectively targets ovarian cancer is a difficult task.…”

ROS Pleiotropy in Melanoma and Local Therapy with Physical Modalities

“…The concentration of the ROS can be tuned by changing the ionization variables and the target exposure time [217], while the ambient air condition was found to have a lower impact [218]. As a mechanism of action, gas plasmaderived ROS modulate the expression of redox-regulating enzymes and pathways [219][220][221] and was found to show combinatorial effects with chemotherapy [222][223][224], radiotherapy [225][226][227], and antibody [228] and topical immunotherapy [229]. We have recently also reported for the first time apoptotic effects in patient-derived melanoma tissues [230] and that ROS-derived oxidative posttranslational protein modifications (oxPTMs) generated with gas plasma technology have immunogenic properties and protect from melanoma growth in vivo [231].…”

Current State of Cold Atmospheric Plasma and Cancer‐Immunity Cycle: Therapeutic Relevance and Overcoming Clinical Limitations Using Hydrogels

“…[ 20–23 ] To this end, there is an effort to understand the main underlying cellular response pathways as this could enable better prediction and improvement of CAP treatment outcome. [ 24–26 ]…”

“…[20][21][22][23] To this end, there is an effort to understand the main underlying cellular response pathways as this could enable better prediction and improvement of CAP treatment outcome. [24][25][26] For cancer treatment to be long-lasting and efficient for different cancer types, it is often not sufficient that it solely provides cytotoxicity to cancer cells. Namely, cancer cells across and within the tumors are heterogeneous and might respond differently to the same treatment.…”