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Cold Atmospheric Plasma Conveys Selectivity Against Hepatocellular Carcinoma Cells via Triggering EGFR(Tyr1068)-Mediated Autophagy.

ABSTRACT: Hepatocellular carcinomas remain as a global health threat given its high mortality rate. We have previously identified the selectivity of cold atmospheric plasma (CAP) against multiple types of malignant tumors and proposed it as a promising onco-therapeutic strategy. Here, we investigated its roles in controlling hepatocellular carcinoma malignancy and one possible driving molecular mechanism. By focusing on post-translational modifications including acetylation, phosphorylation, and ubiquitination, we identified the crosstalk between EGFR acetylation and EGFR(Tyr1068) phosphorylation and their collective roles in determining LC3B ubiquitination and proposed the EGFR/p-JNK/BIRC6/LC3B axis in CAP-triggered autophagy. Our study not only demonstrated the selectivity of CAP against hepatocellular carcinoma malignancy and confirmed its roles as an onco-therapeutic tool but also opened the horizon of translating CAP into clinics toward a broader scope that included human longevity and anti-aging.

SUBMITTER: Wang D

PROVIDER: S-EPMC9292981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cold atmospheric plasma causes a calcium influx in melanoma cells triggering CAP-induced senescence.

Project description:Cold atmospheric plasma (CAP) is a promising approach in anti-cancer therapy, eliminating cancer cells with high selectivity. However, the molecular mechanisms of CAP action are poorly understood. In this study, we investigated CAP effects on calcium homeostasis in melanoma cells. We observed increased cytoplasmic calcium after CAP treatment, which also occurred in the absence of extracellular calcium, indicating the majority of the calcium increase originates from intracellular stores. Application of previously CAP-exposed extracellular solutions also induced cytoplasmic calcium elevations. A substantial fraction of this effect remained when the application was delayed for one hour, indicating the chemical stability of the activating agent(s). Addition of ryanodine and cyclosporin A indicate the involvement of the endoplasmatic reticulum and the mitochondria. Inhibition of the cytoplasmic calcium elevation by the intracellular chelator BAPTA blocked CAP-induced senescence. This finding helps to understand the molecular influence and the mode of action of CAP on tumor cells.

| S-EPMC6030087 | biostudies-literature

Cold Atmospheric Plasma and Silymarin Nanoemulsion Activate Autophagy in Human Melanoma Cells.

Project description:Autophagy is reported as a survival or death-promoting pathway that is highly debatable in different kinds of cancer. Here, we examined the co-effect of cold atmospheric plasma (CAP) and silymarin nanoemulsion (SN) treatment on G-361 human melanoma cells via autophagy induction. The temperature and pH of the media, along with the cell number, were evaluated. The intracellular glucose level and PI3K/mTOR and EGFR downstream pathways were assessed. Autophagy-related genes, related transcriptional factors, and autophagy induction were estimated using confocal microscopy, flow cytometry, and ELISA. CAP treatment increased the temperature and pH of the media, while its combination with SN resulted in a decrease in intracellular ATP with the downregulation of PI3K/AKT/mTOR survival and RAS/MEK transcriptional pathways. Co-treatment blocked downstream paths of survival pathways and reduced PI3K (2 times), mTOR (10 times), EGFR (5 times), HRAS (5 times), and MEK (10 times). CAP and SN co-treated treatment modulates transcriptional factor expressions (ZKSCAN3, TFEB, FOXO1, CRTC2, and CREBBP) and specific genes (BECN-1, AMBRA-1, MAP1LC3A, and SQSTM) related to autophagy induction. CAP and SN together activate autophagy in G-361 cells by activating PI3K/mTOR and EGFR pathways, expressing autophagy-related transcription factors and genes.

| S-EPMC7139470 | biostudies-literature

Pyruvate Plays a Main Role in the Antitumoral Selectivity of Cold Atmospheric Plasma in Osteosarcoma.

Project description:Osteosarcoma (OS) is the most common primary bone tumor but current therapies still have poor prognosis. Cold Atmospheric Plasma (CAP) and Plasma activated media (PAM) have shown potential to eliminate cancer cells in other tumors. It is thought that Reactive Oxygen and Nitrogen species (RONS) in PAM are key players but cell culture media composition alters treatment outcomes and data interpretation due to scavenging of certain RONS. In this work, an atmospheric pressure plasma jet was employed to obtain PAM in the presence or absence of pyruvate and used to treat the SaOS-2 (OS) cell line or hBM-MSC healthy cells. OS cells show higher sensitivity to PAM treatment than healthy cells, both in medium with and without pyruvate, activating apoptosis, DNA damage and deregulating cellular pathways mediated by c-JUN, AKT, AMPK or STAT3. In line with previous works, lack of pyruvate increases cytotoxic potential of PAM affecting cancer and healthy cells by increasing 10-100 times the concentration of H2O2 without altering that of nitrites and thus decreasing CAP anti-tumor selectivity. Suitable conditions for CAP anti-cancer selectivity can be obtained by modifying plasma process parameters (distance, flow, treatment time) to obtain adequate balance of the different RONS in cell culture media.

| S-EPMC6650457 | biostudies-literature

Cold Atmospheric Plasma Boosts Virus Multiplication via EGFR(Tyr1068) Phosphorylation-Mediated Control on Cell Mitophagy.

Project description:Objectives: Vaccination still remains as the most effective approach for preventing infectious diseases such as those caused by virus infection, with cell-based vaccine manufacturing being one flexible solution regarding the spectrum of infectious disorders it can prevent. Rapid cell-based virus propagation can enable high yield of vaccines against viral diseases that may offer critical values in the industry when handling emergent situations such as the ongoing viral disease pandemic. Methods: Through investigating the phenomenon and biological mechanism underlying redox-triggered cell survival towards enhanced viral particle production, this study explores novel strategies for improved yield of viral particles at a reduced cost to meet the increasing demand on cell-based vaccine manufacturing against viral diseases. Results: We found in this study that cold atmospheric plasma (CAP), composed of multiple reactive oxygen and nitrogen species including H2O2, could effectively enhance virus replication via triggering cell mitophagy that was dynamically modulated by the p-EGFR(Tyr1068)/p-Drp1(Ser616) axis using IBRV and MDBK as the virus and cell models, respectively; and removing H2O2 can further enhance virus yield via releasing cells from excessive G0/G1 cell cycle arrest. The observed efficacy of CAP was extended to other viruses such as CDV and CPV. Conclusion: This study provides experimental evidences supporting the use of CAP as a modulator of cell survival including mitophagy and mitochondria dynamics, and makes CAP an interesting and promising tool for enhancing the yield of viral vaccines if translated into the industry.

| S-EPMC9134911 | biostudies-literature

Influence of Cell Type and Culture Medium on Determining Cancer Selectivity of Cold Atmospheric Plasma Treatment.

Project description:Increasing the selectivity of cancer treatments is attractive, as it has the potential to reduce side-effects of therapy. Cold atmospheric plasma (CAP) is a novel cancer treatment that disrupts the intracellular oxidative balance. Several reports claim CAP treatment to be selective, but retrospective analysis of these studies revealed discrepancies in several biological factors and culturing methods. Before CAP can be conclusively stated as a selective cancer treatment, the importance of these factors must be investigated. In this study, we evaluated the influence of the cell type, cancer type, and cell culture medium on direct and indirect CAP treatment. Comparison of cancerous cells with their non-cancerous counterparts was performed under standardized conditions to determine selectivity of treatment. Analysis of seven human cell lines (cancerous: A549, U87, A375, and Malme-3M; non-cancerous: BEAS-2B, HA, and HEMa) and five different cell culture media (DMEM, RPMI1640, AM, BEGM, and DCBM) revealed that the tested parameters strongly influence indirect CAP treatment, while direct treatment was less affected. Taken together, the results of our study demonstrate that cell type, cancer type, and culturing medium must be taken into account before selectivity of CAP treatment can be claimed and overlooking these parameters can easily result in inaccurate conclusions of selectivity.

| S-EPMC6770138 | biostudies-literature

Cold Atmospheric Plasma Modification of Amyloid β.

Project description:Cold atmospheric plasma (CAP) has attracted much attention in the fields of biotechnology and medicine owing to its potential utility in clinical applications. Recently accumulating evidence has demonstrated that CAP influences protein structures. However, there remain open questions regarding the molecular mechanisms behind the CAP-induced structural perturbations of biomacromolecules. Here, we investigated the potential effects of CAP irradiation of amyloid β (Aβ), an amyloidogenic protein associated with Alzheimer's disease. Using nuclear magnetic resonance spectroscopy, we observed gradual spectral changes in Aβ after a 10 s CAP pretreatment, which also suppressed its fibril formation, as revealed by thioflavin T assay. As per mass spectrometric analyses, these effects were attributed to selective oxidation of the methionine residue (Met) at position 35. Interestingly, this modification occurred when Aβ was dissolved into a pre-irradiated buffer, indicating that some reactive species oxidize the Met residue. Our results strongly suggest that the H2O2 generated in the solution by CAP irradiation is responsible for Met oxidation, which inhibits Aβ amyloid formation. The findings of the present study provide fundamental insights into plasma biology, giving clues for developing novel applications of CAP.

| S-EPMC8003251 | biostudies-literature

IFNγ synergies with cold atmospheric plasma in triggering colorectal cancer cell ferroptosis via the IFNγ/IFNR2/APC/TCF4/GPX4 axis.

Project description:Colorectal cancer accounts for the second most common cancer-related lethality. Intestinal stem cells are responsible for enteric homeostasis maintenance that, once being transformed, become colorectal cancer stem cells. Arresting cancer stemness represents an innovative strategy for colorectal cancer management. Using intestinal stem cell organoids as the primary model, we screened common inflammatory cytokines to identify key players targeting cancer stemness. We also explored the downstream signaling that drives the functionalities of the identified cytokine through both experimental investigations and computational predictions. As the results, we identified IFNγ as the key cytokine capable of arresting intestinal stem cells via the IFNγ/IFNGR2/APC/TCF4/GPX4 axis, proposed its role in killing colorectal cancer stem cells via triggering GPX4-dependent ferroptosis, and demonstrated its synergistic anti-cancer effect with cold atmospheric plasma in killing colorectal cancer cells that is worthy to be experimentally validated.

| S-EPMC10522381 | biostudies-literature

Effect of cold atmospheric plasma (CAP) in MCF-7

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-01-24 | GSE131480 | GEO

Antibacterial efficacy of cold atmospheric plasma against Enterococcus faecalis planktonic cultures and biofilms in vitro.

Project description:Nosocomial infections have become a serious threat in our times and are getting more difficult to handle due to increasing development of resistances in bacteria. In this light, cold atmospheric plasma (CAP), which is known to effectively inactivate microorganisms, may be a promising alternative for application in the fields of dentistry and dermatology. CAPs are partly ionised gases, which operate at low temperature and are composed of electrons, ions, excited atoms and molecules, reactive oxygen and nitrogen species. In this study, the effect of CAP generated from ambient air was investigated against Enterococcus faecalis, grown on agar plates or as biofilms cultured for up to 72 h. CAP reduced the colony forming units (CFU) on agar plates by > 7 log10 steps. Treatment of 24 h old biofilms of E. faecalis resulted in CFU-reductions by ≥ 3 log10 steps after CAP treatment for 5 min and by ≥ 5 log10 steps after CAP treatment for 10 min. In biofilm experiments, chlorhexidine (CHX) and UVC radiation served as positive controls and were only slightly more effective than CAP. There was no damage of cytoplasmic membranes upon CAP treatment as shown by spectrometric measurements for release of nucleic acids. Thus, membrane damage seems not to be the primary mechanism of action for CAP towards E. faecalis. Overall, CAP showed pronounced antimicrobial efficacy against E. faecalis on agar plates as well as in biofilms similar to positive controls CHX or UVC.

| S-EPMC6879142 | biostudies-literature

Cold Atmospheric Plasma: A Powerful Tool for Modern Medicine.

Project description:Cold atmospheric plasma use in clinical studies is mainly limited to the treatment of chronic wounds, but its application in a wide range of medical fields is now the goal of many analyses. It is therefore likely that its application spectrum will be expanded in the future. Cold atmospheric plasma has been shown to reduce microbial load without any known significant negative effects on healthy tissues, and this should enhance its possible application to any microbial infection site. It has also been shown to have anti-tumour effects. In addition, it acts proliferatively on stem cells and other cultivated cells, and the highly increased nitric oxide levels have a very important effect on this proliferation. Cold atmospheric plasma use may also have a beneficial effect on immunotherapy in cancer patients. Finally, it is possible that the use of plasma devices will not remain limited to surface structures, because current endeavours to develop sufficiently miniature microplasma devices could very likely lead to its application in subcutaneous and internal structures. This study summarises the available literature on cold plasma action mechanisms and analyses of its current in vivo and in vitro use, primarily in the fields of regenerative and dental medicine and oncology.

| S-EPMC7215620 | biostudies-literature

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