Summary of project PR001941
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001941. The data can be accessed directly via it's Project DOI: 10.21228/M8TM76 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001941 |
| Project DOI: | doi: 10.21228/M8TM76 |
| Project Title: | The shutdown of NADH oxidation via Respiratory Complex I mimics fatty acid biosynthesis inhibition |
| Project Type: | LC-MS Quantitative Analysis |
| Project Summary: | Proliferating cancer cells actively utilize anabolic processes for biomass production, including de novo biosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions. Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of some commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors. Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application. |
| Institute: | Wistar Institute |
| Department: | Molecular and Cellular Oncogenesis Program, Ellen and Ronald Caplan Cancer Center |
| Laboratory: | Schug's Lab |
| Last Name: | Mukha |
| First Name: | Dzmitry |
| Address: | 3601 Spruce St., Philadelphia, Pennsylvania 19104, USA |
| Email: | dmukha@wistar.org |
| Phone: | +12154956903 |
| Funding Source: | This work was supported by grants from the National Institutes of Health (NIH) National Cancer Institute (NCI) DP2 CA249950-01 (Z.T.S.), NIH NCI P01 CA114046 (Z.T.S.), Melanoma Research Foundation 717173 (Z.T.S.), and Susan G. Komen CCR19608782 (Z.T.S.). |
| Publications: | Submission Pending |
| Contributors: | Dzmitry Mukha, Jena Dessain, Seamus O’Connor, Katherine Pniewski, Fabrizio Bertolazzi, Jeet Patel, Mary Mullins, Zachary T. Schug |
Summary of all studies in project PR001941
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003123 | OMM1.3 uveal melanoma cells fed with [U-13C6] glucose and treated with Fasnall for 4 h | Homo sapiens | Wistar Institute | MS | 2024-03-29 | 1 | 23 | Uploaded data (4.1G)* |
| ST003147 | BT-474 cells fed with [13C2] acetate and treated with 1 uM Fasnall or 1 uM GSK2194069 for 24 h | Homo sapiens | Wistar Institute | MS | 2024-04-02 | 1 | 13 | Uploaded data (2.2G)* |
| ST003148 | BT-474 cells fed with [U-13C6] D-glucose or [U-13C5] L-glutamine and treated with Fasnall and GSK2194069 for 24 h | Homo sapiens | Wistar Institute | MS | 2024-04-02 | 1 | 22 | Uploaded data (3.4G)* |
| ST003151 | BT474 breast cancer cell line grown in 20% D2O-containing RPMI-1640 medium treated with Fasnall and GSK2194069 | Homo sapiens | Wistar Institute | MS | 2024-04-02 | 1 | 27 | Uploaded data (6.6G)* |
| ST003152 | Metabolomics analysis of murine xenograft tumors derived from human breast cancer cell line MCF7 1 h after isotopic glucose bolus | Mus musculus | Wistar Institute | MS | 2024-04-02 | 1 | 19 | Uploaded data (3.1G)* |
