Autophagy modulation changes mechano-chemical sensitivity of T24 bladder cancer cells

Maximilian Jobst; Maliha Hossain; Endre Kiss; Janice Bergen; Doris Marko; Giorgia Del Favero

doi:10.1016/j.biopha.2023.115942

Autophagy modulation changes mechano-chemical sensitivity of T24 bladder cancer cells

Biomed Pharmacother. 2024 Jan:170:115942. doi: 10.1016/j.biopha.2023.115942. Epub 2023 Dec 2.

Authors

Maximilian Jobst¹, Maliha Hossain², Endre Kiss³, Janice Bergen¹, Doris Marko², Giorgia Del Favero⁴

Affiliations

¹ Department 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.
² Department of Food Chemistry and Toxicology, University of Vienna Faculty of Chemistry, Währinger Str. 38-40, 1090 Vienna, Austria.
³ Core Facility Multimodal Imaging, University of Vienna Faculty of Chemistry, Währinger Str. 38-40, 1090 Vienna, Austria.
⁴ Department 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. Electronic address: giorgia.del.favero@univie.ac.at.

PMID: 38042111
DOI: 10.1016/j.biopha.2023.115942

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.

Keywords: Autophagy inhibition; Bladder cancer; Calcium signaling; Chemical compounds studied in this article Bafilomycin A1 (PubChem CID: 6436223); Deoxynivalenol (PubChem CID: 40024); Fungal metabolites; Fusaric acid (PubChem CID: 3442); GsMTx-4 (PubChem CID: 90488987); Mechanotransduction; PIEZO1; Wortmannin (PubChem CID: 312145); YODA1 (PubChem CID: 2746822).

MeSH terms

Antineoplastic Agents* / pharmacology
Autophagy
Humans
Ion Channels
Mechanotransduction, Cellular
Urinary Bladder Neoplasms* / drug therapy
Wortmannin / pharmacology

Substances

Wortmannin
Antineoplastic Agents
PIEZO1 protein, human
Ion Channels