The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate
Open accessAbstract
Cancer cells with specific genetic alterations may be highly dependent on certain nutrients for survival, which can inform therapeutic strategies to target these cancer-specific metabolic vulnerabilities. The glutamate/cystine antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT) is overexpressed in several cancers. Contrasting the established pro-survival roles of SLC7A11 under other stress conditions, here we report the unexpected finding that SLC7A11 overexpression enhances cancer cell dependence on glucose and renders cancer cells more sensitive to glucose starvation-induced cell death and, conversely, that SLC7A11 deficiency by either knockdown or pharmacological inhibition promotes cancer cell survival upon glucose starvation. We further show that glucose starvation induces SLC7A11 expression through ATF4 and NRF2 transcription factors and, correspondingly, that ATF4 or NRF2 deficiency also renders cancer cells more resistant to glucose starvation. Finally, we show that SLC7A11 overexpression decreases whereas SLC7A11 deficiency increases intracellular glutamate levels because of SLC7A11-mediated glutamate export and that supplementation of α-ketoglutarate, a key downstream metabolite of glutamate, fully restores survival in SLC7A11 -overexpressing cells under glucose starvation. Together, our results support the notion that both glucose and glutamate have important roles in maintaining cancer cell survival and uncover a previously unappreciated role of SLC7A11 to promote cancer cell dependence on glucose. Our study therefore informs therapeutic strategies to target the metabolic vulnerability in tumors with high SLC7A11 expression.
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Cites
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Self-citationKoppula, P., Zhang, Y., Zhuang, L., & Gan, B. (2018) · Cancer Communications · doi:10.1186/s40880-018-0288-x · Cited by 915
Self-citationmTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation
Zhang, Y., Swanda, R. V., Nie, L., Liu, X., Wang, C., Lee, H., Lei, G., Mao, C., Koppula, P., Cheng, W., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21841-w · Cited by 698
Self-citationThe Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11
Liu, T., Jiang, L., Tavana, O., & Gu, W. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3037 · Cited by 490
Metabolism of Amino Acids in Cancer
Wei, Z., Liu, X., Cheng, C., Yu, W., & Yi, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.603837 · Cited by 429
Metadata
- Authors
- Koppula, P., Zhang, Y., Shi, J., Li, W., & Gan, B.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 292
- Issue
- 34
- Pages
- 14240-14249
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2640064441
- Cited by
- 304
- References
- 11
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Koppula, P., Zhang, Y., Shi, J., Li, W., & Gan, B. (2017). The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m117.798405
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