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Expression, Purification, Crystallization, and Enzyme Assays of Fumarylacetoacetate Hydrolase Domain-Containing Proteins
Published on: June 20, 2019
FASN targeting by G28UCM impairs mitochondrial fatty acid synthesis and reveals a FASN-SDHB synthetic interaction
Nastasia Wilfinger-Lutz1, Kristina M Kuehrer1, Maria J Bueno2
1Internal Medicine I, Medical University Vienna and Comprehensive Cancer Center, Austria.
Abstract:
Metabolic reprogramming in cancer relies on lipid synthesis and mitochondrial function, yet how these processes, other than citrate flux and β-oxidation, intersect remains unclear. While inhibitors of lipogenic pathways have been developed as potential therapeutic agents in cancer therapy, their impact on oxidative metabolism is underexplored. Here, we identify the fatty acid synthase (FASN) inhibitor G28UCM as a compound that additionally destabilizes mitochondrial fatty acid synthase (mtFAS) and succinate dehydrogenase subunit B (SDHB), thereby targeting cytosolic and mitochondrial metabolism. Unexpectedly, the decreased abundance of SDHB was linked to disruption of mtFAS, most notably downregulation of Lipoyl Synthase (LIAS). G28UCM induced profound metabolic stress, including pseudohypoxia, oxidative stress, endoplasmic reticulum stress, and ferroptosis. In contrast, genetic depletion of FASN failed to reproduce these effects. In addition to investigating the mechanism of action of G28UCM, our study revealed a genetic interaction between FASN and SDHB, establishing that their dual but not single loss of function is sufficient to impair tumor growth. The synthetic interaction was conserved across prostate cancer, neuroendocrine tumors, and renal carcinoma cell models, including patient-derived cells, and combined inhibition of FASN and SDH markedly suppressed tumor progression in a breast cancer mouse model. Our findings point to new therapeutic opportunities for FASN inhibition beyond tumor initiation, with particular relevance to cancers associated with malignant SDHB mutations.
Insights
A novel fatty acid synthase (FASN) inhibitor, G28UCM, disrupts both cytosolic and mitochondrial metabolism, inducing significant cancer cell stress. Dual inhibition of FASN and succinate dehydrogenase B (SDHB) shows therapeutic promise across multiple cancer types.
Area of Science:
- Biochemistry
- Cancer Biology
- Metabolic Pathways
Background:
- Metabolic reprogramming is crucial for cancer growth, involving lipid synthesis and mitochondrial function.
- The interplay between lipogenesis and oxidative metabolism in cancer is not fully understood.
- Lipid synthesis inhibitors' effects on oxidative metabolism require further investigation.
Purpose of the Study:
- To identify novel therapeutic targets by investigating the impact of FASN inhibition on cancer metabolism.
- To explore the mechanism of action of the FASN inhibitor G28UCM.
- To evaluate the therapeutic potential of combined FASN and SDHB inhibition in cancer.
Main Methods:
- Utilized the FASN inhibitor G28UCM to assess its effects on cellular metabolism.
- Investigated the impact of G28UCM on mitochondrial fatty acid synthase (mtFAS) and succinate dehydrogenase subunit B (SDHB).
- Performed genetic depletion of FASN and assessed tumor growth in preclinical cancer models.
Main Results:
- G28UCM destabilized mtFAS and SDHB, leading to metabolic stress, including pseudohypoxia and ferroptosis.
- Genetic FASN depletion did not replicate G28UCM's effects, suggesting a broader mechanism.
- Dual inhibition of FASN and SDHB demonstrated synthetic lethality and suppressed tumor growth in vitro and in vivo.
Conclusions:
- G28UCM targets both cytosolic and mitochondrial metabolism, offering a unique therapeutic strategy.
- A synthetic interaction between FASN and SDHB is identified, highlighting a novel therapeutic vulnerability.
- Combined FASN and SDH inhibition presents a promising approach for treating cancers, particularly those with SDHB mutations.
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