Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 19; pp. 9433 - 9442
• Main Authors: Lim, Jonathan K. M., Delaidelli, Alberto, Minaker, Sean W., Zhang, Hai-Feng, Colovic, Milena, Yang, Hua, Negri, Gian Luca, von Karstedt, Silvia, Lockwood, William W., Schaffer, Paul, Leprivier, Gabriel, Sorensen, Poul H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.05.2019
• Series: PNAS Plus
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Amino Acid Transport System y+ - biosynthesis; Amino Acid Transport System y+ - genetics; Animals; Antioxidants; Biological Sciences; Biosynthesis; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cystine; Downstream effects; Endoplasmic reticulum; Endoplasmic Reticulum Stress; ETS protein; Female; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gene expression; Gene regulation; Genetic transformation; Homeostasis; Intracellular; MAP Kinase Signaling System; Mice; Mice, Knockout; Mice, Nude; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; NIH 3T3 Cells; Oxidation-Reduction; Oxidative Stress; PNAS Plus; Proto-Oncogene Protein c-ets-1 - genetics; Proto-Oncogene Protein c-ets-1 - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Proto-oncogenes; Raf protein; Reactive oxygen species; Signal transduction; Signaling; Transcription factors; Transformed cells; Tumorigenicity; Tumors; Xenografts; Xenotransplantation; xCT; oncogene; RAS; antioxidants
• DOI: 10.1073/pnas.1821323116
• ISSN: 0027-8424

The RAS family of proto-oncogenes are among the most commonly mutated genes in human cancers and predict poor clinical outcome. Several mechanisms underlying oncogenic RAS transformation are well documented, including constitutive signaling through the RAF-MEK-ERK proproliferative pathway as well as the PI3K-AKT prosurvival pathway. Notably, control of redox balance has also been proposed to contribute to RAS transformation. However, how homeostasis between reactive oxygen species (ROS) and antioxidants, which have opposing effects in the cell, ultimately influence RAS-mediated transformation and tumor progression is still a matter of debate and the mechanisms involved have not been fully elucidated. Here, we show that oncogenic KRAS protects fibroblasts from oxidative stress by enhancing intracellular GSH levels. Using a whole transcriptome approach,we discovered that this is attributable to transcriptional up-regulation of xCT, the gene encoding the cystine/glutamate antiporter. This is in line with the function of xCT, which mediates the uptake of cystine, a precursor for GSH biosynthesis. Moreover, our results reveal that the ETS-1 transcription factor downstream of the RAS-RAF-MEK-ERK signaling cascade directly transactivates the xCT promoter in synergy with the ATF4 endoplasmic reticulum stress-associated transcription factor. Strikingly, xCT was found to be essential for oncogenic KRAS-mediated transformation in vitro and in vivo bymitigating oxidative stress, as knockdown of xCT strongly impaired growth of tumor xenografts established from KRAS-transformed cells. Overall, this study uncovers a mechanism by which oncogenic RAS preserves intracellular redox balance and identifies an unexpected role for xCT in supporting RAS-induced transformation and tumorigenicity.