Summary of project PR001663
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 PR001663. The data can be accessed directly via it's Project DOI: 10.21228/M8R72W This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001663 |
| Project DOI: | doi: 10.21228/M8R72W |
| Project Title: | Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss |
| Project Summary: | SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers.we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers. |
| Institute: | McGill University |
| Department: | Biochemistry |
| Laboratory: | Sidong Huang Lab |
| Last Name: | Fu |
| First Name: | Zheng |
| Address: | McIntyre Medical Sciences Building |
| Email: | zheng.fu2@mail.mcgill.ca |
| Phone: | 5145869072 |
Summary of all studies in project PR001663
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST002578 | Steady State Metabolomics Study in SMARCA4 mutant(BIN-67) cells cultured in the absence of glucose or glutamine | Homo sapiens | McGill University | MS | 2023-05-22 | 1 | 36 | Uploaded data (65.4M)* |
| ST002586 | Stable isotope tracer analysis (SITA) using 13C6-glucose and 13C5-glutamine measured by GC/MS in BIN-67 cells ± SMARCA4 restoration | Homo sapiens | McGill University | MS | 2023-05-22 | 1 | 25 | Uploaded data (78.7M)* |
| ST002587 | Stable isotope tracer analysis (SITA) using 13C6-glucose and 13C5-glutamine measured by GC/MS in H1703 cells ± SMARCA4/A2 restoration | Homo sapiens | McGill University | MS | 2023-05-22 | 1 | 45 | Uploaded data (154.7M)* |
