Dataset Information

Fungal extract screening reveals malformin C to preferentially kill glioblastoma cells via concerted induction of proteotoxic stress and autophagic flux blockade

ABSTRACT: Azide-labelled malformin C or DMSO was incubated with protein lysate from patient derived glioblastoma stem-like cells (NCH421k), and a pulldown of the compound with Dibenzocyclooctyne (DBCO) agarose was performed in order to identify interacting proteins.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Meningioma Cell, Stem Cell

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Emma Phillips

LAB HEAD: Violaine Goidts

PROVIDER: PXD046258 | Pride | 2025-05-06

REPOSITORIES: Pride

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Malformin C preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade.

Phillips Emma E van Enk Sizèd S Kildgaard Sara S Schlue Silja S Göttmann Mona M Jennings Victoria V Bethke Frederic F Müller Gabriele G Herold-Mende Christel C Pastor-Flores Daniel D Schneider Martin M Helm Dominic D Ostenfeld Larsen Thomas T Goidts Violaine V

Molecular oncology 20241027 3

Glioblastoma is a highly aggressive brain tumor for which there is no cure. The dire prognosis of this disease is largely attributable to a high level of heterogeneity, including the presence of a subpopulation of tumor-initiating glioblastoma stem-like cells (GSCs), which are refractory to chemo- and radiotherapy. Here, in an unbiased marine-derived fungal extract screen, together with bioguided dereplication based on high-resolution mass spectrometry, we identified malformin C to preferentiall ...[more]

PMID: 39462997

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Project description:Neurons and astrocytes face unique demands on their proteome to enable proper function and survival of the nervous system. Consequently, both cell types are critically dependent on robust quality control pathways such as macroautophagy (hereafter referred to as autophagy) and the ubiquitin-proteasome system (UPS). We previously reported that autophagy is differentially regulated in astrocytes and neurons in the context of metabolic stress, but less is understood in the context of proteotoxic stress induced by inhibition of the UPS. Dysfunction of the proteasome or autophagy has been linked to the progression of various neurodegenerative diseases. Therefore, in this study, we explored the connection between autophagy and the proteasome in primary astrocytes and neurons. Prior studies largely in non-neural models report a compensatory relationship whereby inhibition of the UPS stimulates autophagy. To our surprise, inhibition of the proteasome did not robustly upregulate autophagy in astrocytes or neurons. In fact, the effects on autophagy are modest particularly in comparison to paradigms of metabolic stress. Rather, we find that UPS inhibition in astrocytes induces formation of Ub-positive aggregates that harbor the selective autophagy receptor, SQSTM1/p62, but these structures were not productive substrates for autophagy. By contrast, we observed a significant increase in lysosomal degradation in astrocytes in response to UPS inhibition, but this stimulation was not sufficient to reduce total SQSTM1 levels. Last, UPS inhibition was more toxic in neurons compared to astrocytes, suggesting a cell type-specific vulnerability to proteotoxic stress.Abbreviations: Baf A1: bafilomycin A1; CQ: chloroquine; Epox: epoxomicin; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; p-ULK1: phospho-ULK1; SQSTM1/p62: sequestosome 1; Ub: ubiquitin; ULK1: unc-51 like kinase 1; UPS: ubiquitin-proteasome system.

Project description:BackgroundInorganic arsenic (iAs) is an environmental toxicant associated with an increased risk of prostate cancer in chronically exposed populations worldwide. However, the biological mechanisms underlying iAs-induced prostate carcinogenesis remain unclear.ObjectivesWe studied how iAs affects normal human prostate stem-progenitor cells (PrSPCs) and drives transformation and interrogated the molecular mechanisms involved.MethodsPrSPCs were enriched by spheroid culture from normal human primary or immortalized prostate epithelial cells, and their differentiation capability was evaluated by organoid culture. Microarray analysis was conducted to identify iAs-dysregulated genes, and lentiviral infection was used for stable manipulation of identified genes. Soft agar colony growth assays were applied to examine iAs-induced transformation. For in vivo study, PrSPCs mixed with rat urogenital sinus mesenchyme were grafted under the renal capsule of nude mice to generate prostatelike tissues, and mice were exposed to 5 ppm (∼65μM) iAs in drinking water for 3 months.ResultsLow-dose iAs (1μM) disturbed PrSPC homeostasis in vitro, leading to increased self-renewal and suppressed differentiation. Transcriptomic analysis indicated that iAs activated oncogenic pathways in PrSPCs, including the KEAP1-NRF2 pathway. Further, iAs-exposed proliferative progenitor cells exhibited NRF2 pathway activation that was sustained in their progeny cells. Knockdown of NRF2 inhibited spheroid formation by driving PrSPC differentiation, whereas its activation enhanced spheroid growth. Importantly, iAs-induced transformation was suppressed by NRF2 knockdown. Mechanistically, iAs suppressed Vacuolar ATPase subunit VMA5 expression, impairing lysosome acidification and inhibiting autophagic protein degradation including p62, which further activated NRF2. In vivo, chronic iAs exposure activated NRF2 in both epithelial and stroma cells of chimeric human prostate grafts and induced premalignant events.ConclusionsLow-dose iAs increased self-renewal and decreased differentiation of human PrSPCs by activating the p62-NRF2 axis, resulting in epithelial cell transformation. NRF2 is activated by iAs through specific autophagic flux blockade in progenitor cells, which may have potential therapeutic implications. https://doi.org/10.1289/EHP6471.

			Action	DRS
	UP000005640_9606.fasta	Fasta
	oecf1-EP0478-01.raw	Raw
	oecf1-EP0478-02.raw	Raw
	oecf1-EP0478-03.raw	Raw
	oecf1-EP0478-04.raw	Raw