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Updated: Jul 9, 2025
Quantitative Analysis of Autophagy using Advanced 3D Fluorescence Microscopy
Published on: May 3, 2013
Autophagy modulation changes mechano-chemical sensitivity of T24 bladder cancer cells
Maximilian Jobst1, Maliha Hossain2, Endre Kiss3
1Department of Food Chemistry and Toxicology, University of Vienna Faculty of Chemistry, Währinger Str. 38-40, 1090 Vienna, Austria; Core Facility Multimodal Imaging, University of Vienna Faculty of Chemistry, Währinger Str. 38-40, 1090 Vienna, Austria; University of Vienna, Vienna Doctoral School in Chemistry (DoSChem), Währinger Str. 42, 1090 Vienna, Austria.
Abstract:
Bladder cancer cells possess unique adaptive capabilities: shaped by their environment, cells face a complex chemical mixture of metabolites and xenobiotics accompanied by physiological mechanical cues. These responses might translate into resistance to chemotherapeutical regimens and can largely rely on autophagy. Considering molecules capable of rewiring tumor plasticity, compounds of natural origin promise to offer valuable options. Fungal derived metabolites, such as bafilomycin and wortmannin are widely acknowledged as autophagy inhibitors. Here, their potential to tune bladder cancer cells´ adaptability to chemical and physical stimuli was assessed. Additionally, dietary occurring mycotoxins were also investigated, namely deoxynivalenol (DON, 0.1-10 µM) and fusaric acid (FA, 0.1-1 mM). Endowing a Janus' face behavior, DON and FA are on the one side described as toxins with detrimental health effects. Concomitantly, they are also explored experimentally for selective pharmacological applications including anticancer activities. In non-cytotoxic concentrations, bafilomycin (BAFI, 1-10 nM) and wortmannin (WORT, 1 µM) modified cell morphology and reduced cancer cell migration. Application of shear stress and inhibition of mechano-gated PIEZO channels reduced cellular sensitivity to BAFI treatment (1 nM). Similarly, for FA (0.5 mM) PIEZO1 expression and inhibition largely aligned with the modulatory potential on cancer cells motility. Additionally, this study highlighted that the activity profile of compounds with similar cytotoxic potential (e.g. co-incubation DON with BAFI or FA with WORT) can diverge substantially in the regulation of cell mechanotransduction. Considering the interdependence between tumor progression and response to mechanical cues, these data promise to provide a novel viewpoint for the study of chemoresistance and associated pathways.
Insights
Natural compounds like bafilomycin and wortmannin, along with mycotoxins deoxynivalenol and fusaric acid, were studied for their effects on bladder cancer cell adaptability. These compounds influence cell behavior and migration, offering potential new avenues for cancer therapy research.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Bladder cancer cells adapt to environmental chemical and mechanical cues, potentially leading to chemotherapy resistance.
- Autophagy plays a significant role in cancer cell adaptation and resistance.
- Natural compounds, including fungal metabolites and mycotoxins, are being explored for their therapeutic potential in cancer.
Purpose of the Study:
- To investigate the potential of fungal-derived autophagy inhibitors (bafilomycin, wortmannin) and mycotoxins (deoxynivalenol, fusaric acid) to modulate bladder cancer cell adaptability.
- To assess the impact of these compounds on cell morphology, migration, and response to mechanical stimuli.
- To explore the role of PIEZO channels in mediating the effects of these compounds on cancer cells.
Main Methods:
- Non-cytotoxic concentrations of bafilomycin (BAFI), wortmannin (WORT), deoxynivalenol (DON), and fusaric acid (FA) were applied to bladder cancer cells.
- Cell morphology and migration were analyzed.
- The effects of shear stress and PIEZO channel inhibition on cellular responses to BAFI and FA were investigated.
- Combinations of compounds with similar cytotoxic potential were tested.
Main Results:
- BAFI and WORT modified cell morphology and reduced migration in non-cytotoxic concentrations.
- Shear stress and PIEZO channel inhibition altered cellular sensitivity to BAFI.
- FA's modulatory effects on cell motility were linked to PIEZO1 expression and inhibition.
- Different compound combinations exhibited distinct effects on cell mechanotransduction despite similar cytotoxicity.
Conclusions:
- Fungal metabolites and mycotoxins can significantly influence bladder cancer cell adaptability and mechanotransduction.
- PIEZO channels are involved in mediating the effects of certain compounds on cancer cell motility.
- These findings offer a novel perspective on chemoresistance and associated pathways, highlighting the potential of natural compounds in cancer research.
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