Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.10.31.466636

Air plasma-activated medium exerts tumor-specific cytotoxicity via the oxidative stress-induced perinuclear mitochondrial clustering

Suzuki-Karasaki, M.·Ando, T.·Ochiai, Y.·Kawahara, K.·Nakayama, H.·Suzuki-Karasaki, Y.
View original source ↗Export metadata ↓

Abstract

Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy eliminating cancers effectively and safely is the current clinical choice. Since aggressive tumors have inherent or acquired resistance to multidisciplinary therapies targeting apoptosis, tumor-specific induction of another cell death modality is a promising avenue to meet the goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can induce cell death in OS and OC via a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) because of the characteristic unipolar mitochondrial perinuclear aggregation. APAM had potent antitumor activity both in vitro and in vivo. APAM caused apoptosis, necrotic cell death, and autophagy. APAM contained hydrogen peroxide and increased mitochondrial ROS (mROS), while the antioxidant N-acetylcysteine (NAC) prevented cell death. MPMC occurred following mitochondrial fragmentation coinciding with nuclear damages. MPMC was accompanied by the tubulin network remodeling and mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC and the microtubule inhibitor, Nocodazole. Increased Cardiolipin (CL) oxidation was also seen, and NAC and the peroxy radical scavenger Ferrostatin-1 prevented it. In contrast, in fibroblasts, APAM induced minimal cell death, mROS generation, mLPO accumulation, CL oxidation, and MPMC. These results suggest that MPMC is a tumor-specific cause of cell death via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC might serve as a promising target for exerting tumor-specific cytotoxicity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/466636v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1118e2corg.highwire.dtl.DTLVardef@18cf99corg.highwire.dtl.DTLVardef@57a7edorg.highwire.dtl.DTLVardef@d1f447_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Suzuki-Karasaki, M., Ando, T., Ochiai, Y., Kawahara, K., Nakayama, H., Suzuki-Karasaki, Y.. 2021-11-01. Air plasma-activated medium exerts tumor-specific cytotoxicity via the oxidative stress-induced perinuclear mitochondrial clustering. https://doi.org/10.1101/2021.10.31.466636

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression

Mesenchymal traits are associated with poor prognosis in Pancreatic Ductal Adenocarcinoma (PDA), but direct targeting of mesenchymal tumor cells remains a challenge. Metabolic profiling of tumor cells isolated from murine PDA and liver metastases (LM) revealed that LM rely more on the methionine cycle than does primary PDA. This metabolic shift was specifically associated with increased activation of the methionine cycle in mesenchymal tumor cells compared to differentiated tumor cells. We show that the targeting of the key enzyme of the methionine cycle S-adenosylhomocysteine hydrolase (SAHH) in mesenchymal cells lowers the levels of homocysteine (Hcy) and glutathione, resulting in reduced antioxidant capacity, deregulated intracellular calcium homeostasis, and ultimately loss of mesenchymal markers. Together, these events decrease cell proliferation and invasion, blunting the tumorigenic and metastatic potential of SAHH-deficient cells, eventually impeding tumor growth and progression of the metastatic disease. Clinically, the high expression of SAHH in patients with mesenchymal PDA is correlated with poor survival, positioning SAHH as a potential therapeutic target to impede the pro-metastatic, mesenchymal phenotype of PDA.

cancer biology↗
bioRxiv2026

Arrest-associated transcriptional programmes outweigh apoptosis-associated programmes in treatment-naive pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is driven by mutant KRAS, and RAS inhibitors now extend survival in previously treated metastatic disease. Whether treatment shrinks a tumour or only halts its growth depends partly on whether cancer cells die or stop dividing, yet how untreated PDAC cells are balanced between these programmes is unknown. Aims: We aimed to characterise the balance between apoptosis-associated and arrest-associated transcriptional programmes in treatment-naive PDAC and to examine their relationships with tumour subtype, TGM2 expression, tissue organisation, survival and drug sensitivity. Methods and results: We scored 52,999 malignant cells from 18 untreated patients in the Hwang atlas using a transcriptional contrast between genes associated with apoptosis and genes associated with resistance to apoptosis or cell-cycle arrest. In every patient the contrast was shifted toward the arrest-associated side: using equality between the two sides as the dividing threshold, 86.3% of cells with an informative score fell on that side, although the proportion depends on the threshold chosen. The shift recurred in the independent Steele atlas (median 71.6% per sample, range 37.1% to 90.8%). In the discovery cohort, tumours with higher basal-like scores had fewer arrest-side cells, and TGM2 expression was modestly higher on the arrest-associated side in both cohorts. The contrast did not track cell-line drug sensitivity or survival in bulk tumours. Conclusion: Untreated PDAC cells show a reproducible transcriptional bias toward anti-apoptotic and cell-cycle-arrest programmes. Whether this bias predicts cellular responses to treatment remains to be tested.

cancer biology↗
bioRxiv2026

Quantitative live imaging reveals region-dependent medulloblastoma disseminationin the zebrafish brain

Medulloblastoma is the most common malignant pediatric brain tumor, and relapse is frequently driven by dissemination within the central nervous system. Yet the early dynamics of tumor spread remain difficult to resolve in vivo. Here, we orthotopically transplanted human medulloblastoma cells into larval zebrafish and followed individual xenografts by longitudinal high-resolution confocal imaging. ONS-76 showed particularly robust dissemination, with hindbrain tumors spreading into the developing cerebellum in 81.5% of larvae, more than fourfold the frequency observed for forebrain or midbrain tumors. Disseminating cells extended along brain-surface and leptomeningeal-like regions and frequently associated with cerebral vasculature. Quantitative analysis of tumor area, perimeter, compactness, convex hull area, and fractal dimension captured changes in growth and spatial complexity over time. Dasatinib reduced tumor expansion and dissemination-related features in a concentration-dependent manner, while higher doses revealed host toxicity. These findings establish a powerful in vivo model for resolving medulloblastoma dissemination and therapeutic response.

cancer biology↗