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Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma
Claudio Pulito1, Etleva Korita1, Andrea Sacconi1
1Oncogenomic and Epigenetic Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144, Rome, Italy.
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.
Insights
Dropwort extract shows promise in fighting Malignant Pleural Mesothelioma (MPM) by inhibiting cancer cell growth and targeting the HIPPO pathway. This natural compound offers potential for new MPM chemo-preventive strategies.
Area of Science:
- Oncology
- Natural Product Chemistry
- Molecular Biology
Background:
- Malignant Pleural Mesothelioma (MPM) therapies have shown limited success in improving patient survival.
- Key genes in MPM are often mutated within the HIPPO tumor suppressor pathway.
Purpose of the Study:
- To investigate the anticancer effects of Filipendula vulgaris (Dropwort) extract on MPM.
- To elucidate the molecular mechanisms underlying Dropwort's action, focusing on the HIPPO pathway.
Main Methods:
- In vitro and in vivo models of MPM were used to assess Dropwort's efficacy.
- Metabolomic profiling and phosphoarray analysis were employed to understand Dropwort's mechanism of action.
- YAP and TAZ protein ubiquitination was investigated as a potential target.
Main Results:
- Dropwort significantly reduced MPM cell proliferation, viability, migration, and tumor growth.
- Dropwort demonstrated synergistic effects with Cisplatin and Pemetrexed.
- Metabolomic analysis indicated Dropwort impacts glycolysis, the tricarboxylic acid cycle, and lipid metabolism.
- Dropwort promotes YAP and TAZ protein ubiquitination, suggesting HIPPO pathway involvement.
Conclusions:
- Dropwort extract exhibits significant anticancer properties against MPM.
- Dropwort shows potential as a source of natural compounds for MPM management.
- Targeting the HIPPO pathway with Dropwort offers chemo-preventive and anticancer implications for MPM.
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