Oncogenic KRAS mutations enhance amino acid uptake by colorectal cancer cells via the hippo signaling effector YAP1

• Main Authors: Palanivel Kandasamy, Inti Zlobec, Damian T. Nydegger, Jonai Pujol‐Giménez, Rajesh Bhardwaj, Senji Shirasawa, Toshiyuki Tsunoda, Matthias A. Hediger
• Format: Article
• Language: English
• Published: Wiley 2021-10-01
• Series: Molecular Oncology
• Subjects: amino acid transporters; oncogene; SLC1A5/ASCT2; SLC38A2/SNAT2; SLC7A5/LAT1; solute carriers
• Online Access: https://doi.org/10.1002/1878-0261.12999
• ISSN: 1574-7891; 1878-0261

Oncogenic KRAS mutations develop unique metabolic dependencies on nutrients to support tumor metabolism and cell proliferation. In particular, KRAS mutant cancer cells exploit amino acids (AAs) such as glutamine and leucine, to accelerate energy metabolism, redox balance through glutathione synthesis and macromolecule biosynthesis. However, the identities of the amino acid transporters (AATs) that are prominently upregulated in KRAS mutant cancer cells, and the mechanism regulating their expression have not yet been systematically investigated. Here, we report that the majority of the KRAS mutant colorectal cancer (CRC) cells upregulate selected AATs (SLC7A5/LAT1, SLC38A2/SNAT2, and SLC1A5/ASCT2), which correlates with enhanced uptake of AAs such as glutamine and leucine. Consistently, knockdown of oncogenic KRAS downregulated the expression of AATs, thereby decreasing the levels of amino acids taken up by CRC cells. Moreover, overexpression of mutant KRAS upregulated the expression of AATs (SLC7A5/LAT1, SLC38A2/SNAT2, and SLC1A5/ASCT2) in KRAS wild‐type CRC cells and mouse embryonic fibroblasts. In addition, we show that the YAP1 (Yes‐associated protein 1) transcriptional coactivator accounts for increased expression of AATs and mTOR activation in KRAS mutant CRC cells. Specific knockdown of AATs by shRNAs or pharmacological blockage of AATs effectively inhibited AA uptake, mTOR activation, and cell proliferation. Collectively, we conclude that oncogenic KRAS mutations enhance the expression of AATs via the hippo effector YAP1, leading to mTOR activation and CRC cell proliferation.