Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma

Our plain-English summary of Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma, by C. Pulito, E. Korita, A. Sacconi, et al (Journal of Experimental & Clinical Cancer Research, 2019).

The study

• Authors: C. Pulito, E. Korita, A. Sacconi, M. Valerio, L. Casadei, F. Lo Sardo, F. Mori, M. Ferraiuolo, G. Grasso, A. Maidecchi, J. Lucci, M. Sudol, P. Muti, G. Blandino, S. Strano
• Journal: Journal of Experimental & Clinical Cancer Research
• Published: 2019;38(1):349
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Over the past decade, newly designed cancer therapies have not significantly improved the survival of patients diagnosed with Malignant Pleural Mesothelioma (MPM). Among a limited number of genes that are frequently mutated in MPM several of them encode proteins that belong to the HIPPO tumor suppressor pathway.

Methods: The anticancer effects of the top flower standardized extract of Filipendula vulgaris (Dropwort) were characterized in "in vitro" and "in vivo" models of MPM. At the molecular level, two "omic" approaches were used to investigate Dropwort anticancer mechanism of action: a metabolomic profiling and a phosphoarray analysis.

Results: We found that Dropwort significantly reduced cell proliferation, viability, migration and in vivo tumor growth of MPM cell lines. Notably, Dropwort affected viability of tumor-initiating MPM cells and synergized with Cisplatin and Pemetrexed in vitro. Metabolomic profiling revealed that Dropwort treatment affected both glycolysis/tricarboxylic acid cycle as for the decreased consumption of glucose, pyruvate, succinate and acetate, and the lipid metabolism. We also document that Dropwort exerted its anticancer effects, at least partially, promoting YAP and TAZ protein ubiquitination.

Conclusions: Our findings reveal that Dropwort is a promising source of natural compound(s) for targeting the HIPPO pathway with chemo-preventive and anticancer implications for MPM management.

In plain English

This was a laboratory study, not a study of people. The authors tested a standardized extract from the flowering tops of the plant Filipendula vulgaris (dropwort). They used four human malignant pleural mesothelioma cell lines, untransformed human mesothelial cells, and CD1 mice carrying transplanted mesothelioma tumors, in groups of 6 mice. The study did not examine asbestos exposure. The extract reduced the viability of the mesothelioma cells in a dose dependent manner, and the normal mesothelial cells were more resistant. In mesothelioma cells, the extract also reduced migration and invasion, and it affected the viability of a subgroup of cells with high ALDH activity. In mice, extract given in drinking water inhibited tumor growth in a dose dependent manner, similar to the drug pemetrexed. Tumors in treated mice showed more than 30% lower levels of Ki67, a marker of cell growth. In cell experiments, the extract worked together with cisplatin and pemetrexed. It also lowered glucose consumption and increased the tagging of the YAP and TAZ proteins for breakdown. The authors concluded that dropwort is a promising source of natural compounds for targeting the HIPPO pathway in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using human cancer cell lines (in vitro) and mice with transplanted tumors (in vivo)
• Who was studied: Human malignant pleural mesothelioma cell lines MPP-89, NCI-2052, MSTO-211H and NCI-H28; untransformed human mesothelial cells (HMC); CD1 mice subcutaneously transplanted with MSTO-211H cells, in groups of 6
• Exposure: No asbestos exposure was studied. The treatment tested was a standardized dropwort extract at 3 to 200 μg/ml in cells for 72 h, and in mice at 25, 50 and 75 mg/ml in drinking water daily for three weeks. It was compared with vehicle and with pemetrexed 100 mg/kg.
• Main results:
  • The extract reduced the viability of mesothelioma cell lines in a dose dependent manner. Untransformed mesothelial cells (HMC) were more resistant.
  • Untreated MSTO-211H cells included 10% ALDH-bright cells. The extract affected the viability of this subpopulation in a dose dependent manner.
  • MSTO-211H cells pre-treated with extract engrafted less efficiently in mice than control cells.
  • In mice with transplanted tumors, the extract inhibited tumor growth in a dose dependent manner. Pemetrexed produced a similar reduction.
  • Tumors from all extract-treated groups of mice showed a reduction of more than 30% in Ki67 expression compared with untreated mice.
  • In cell experiments, the extract increased the cell killing caused by cisplatin and by pemetrexed.
  • In MSTO-211H cells, the extract caused lower consumption of glucose, pyruvate and succinate and lower production of acetate. It also reduced phosphorylated mTOR, p70S6 and S6.
  • The extract did not change YAP/TAZ transcript levels but reduced YAP and TAZ protein, and it increased ubiquitination of both proteins.
  • Cells with low TAZ or TEAD levels were killed more readily by the extract than control cells. Cells with high YAP, TAZ or TEAD expression were more resistant.
  • Of the single extract components tested, quercetin, but not gallic acid, reduced YAP and TAZ protein levels in MSTO-211H cells.
• The authors' conclusion: The authors concluded that dropwort is a promising source of natural compound(s) for targeting the HIPPO pathway, with chemo-preventive and anticancer implications for malignant pleural mesothelioma management.
• Limitations the authors state:
  • Because the extract is complex, the authors could not measure the effective compound. Mouse doses refer to total extract and were translated from cell experiments.
  • The authors state that the complete mechanism of the extract's action still needs to be identified.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Cisplatin, Pemetrexed (Alimta).

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• The PERK/ATF4 pathway is required for metabolic reprogramming and progressive lung fibrosis — J. Pandey, J.L. Larson-Casey, et al. (2025)
• Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers — E.A. Chapeau, L. Sansregret, et al. (2024)

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