Summary of Study ST002586
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
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST002586 |
| Study Title | Stable isotope tracer analysis (SITA) using 13C6-glucose and 13C5-glutamine measured by GC/MS in BIN-67 cells ± SMARCA4 restoration |
| Study Summary | SMARCA4/2-loss drives the metabolic shift preferring glutamine than glucose to sustain the TCA cycle. SITA using 13C6-glucose confirmed that glucose uptake was increased in BIN-67 cells upon SMARCA4-restoration, leading to overall increased metabolic flux through glucose (lactate) and TCA cycle intermediates (citrate, fumarate, malate, aspartate) via pyruvate carboxylation.Conversely, the 13C5-glutamine SITA in BIN-67 cells revealed that SMARCA4-restoration decreased glutamine uptake and utilization via glutaminolysis to fuel the TCA cycle as indicated by reduced glutamine metabolites (glutamate, α-KG, m+5 metabolites) and TCA cycle intermediates (succinate, fumarate, malate, aspartate, m+4 metabolites) |
| Institute | McGill University |
| Department | Biochemistry |
| Laboratory | Sidong Huang Lab |
| Last Name | Fu |
| First Name | Zheng |
| Address | McIntyre Medical Sciences Building, 3655 promenade Sir-William-Osler |
| zheng.fu2@mail.mcgill.ca | |
| Phone | 5143985446 |
| Submit Date | 2023-04-25 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzXML |
| Analysis Type Detail | GC-MS |
| Release Date | 2023-05-22 |
| Release Version | 1 |
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Project:
| 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 |
