Universität zu Köln

Lim, Jonathan K. M., Delaidelli, Alberto, Minaker, Sean W., Zhang, Hai-Feng, Colovic, Milena ORCID: 0000-0001-8686-0084, Yang, Hua, Negri, Gian Luca ORCID: 0000-0001-7722-8888, von Karstedt, Silvia, Lockwood, William W., Schaffer, Paul, Leprivier, Gabriel and Sorensen, Poul H. (2019). Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance. Proc. Natl. Acad. Sci. U. S. A., 116 (19). S. 9433 - 9443. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

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 by mitigating oxidative stress, as knock-down 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lim, Jonathan K. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Delaidelli, Alberto UNSPECIFIED UNSPECIFIED UNSPECIFIED Minaker, Sean W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Hai-Feng UNSPECIFIED UNSPECIFIED UNSPECIFIED Colovic, Milena UNSPECIFIED orcid.org/0000-0001-8686-0084 UNSPECIFIED Yang, Hua UNSPECIFIED UNSPECIFIED UNSPECIFIED Negri, Gian Luca UNSPECIFIED orcid.org/0000-0001-7722-8888 UNSPECIFIED von Karstedt, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Lockwood, William W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaffer, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Leprivier, Gabriel UNSPECIFIED UNSPECIFIED UNSPECIFIED Sorensen, Poul H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-148482
DOI:	10.1073/pnas.1821323116
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	116
Number:	19
Page Range:	S. 9433 - 9443
Date:	2019
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL LUNG-CANCER; OXIDATIVE STRESS; SIGNALING PATHWAYS; TRANSPORTER GENE; ROS GENERATION; KRAS; ACID; PROMOTES; SENSITIVITY; GROWTH Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14848