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

Kandasamy, Palanivel; Zlobec, Inti; Nydegger, Damian T.; Pujol-Gimenez, Jonai; Bhardwaj, Rajesh; Shirasawa, Senji; Tsunoda, Toshiyuki; Hediger, Matthias A. (2021). Oncogenic KRAS mutations enhance amino acid uptake by colorectal cancer cells via the hippo signaling effector YAP1. Molecular oncology, 15(10), pp. 2782-2800. Wiley 10.1002/1878-0261.12999

[img]
Preview
Text
Molecular_Oncology_-_2021_-_Kandasamy_-_Oncogenic_KRAS_mutations_enhance_amino_acid_uptake_by_colorectal_cancer_cells_via.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (5MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie
04 Faculty of Medicine > Service Sector > Institute of Pathology > Translational Research Unit

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Kandasamy, Palanivel; Zlobec, Inti; Nydegger, Damian Tobias; Pujol Gimenez, Jonai; Bhardwaj, Rajesh and Hediger, Matthias

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1878-0261

Publisher:

Wiley

Language:

English

Submitter:

Verena de Serra Frazao-Bill

Date Deposited:

12 Jan 2022 14:30

Last Modified:

12 Jan 2022 14:34

Publisher DOI:

10.1002/1878-0261.12999

PubMed ID:

34003553

Uncontrolled Keywords:

SLC1A5/ASCT2 SLC38A2/SNAT2 SLC7A5/LAT1 amino acid transporters oncogene solute carriers

BORIS DOI:

10.48350/162876

URI:

https://boris.unibe.ch/id/eprint/162876

Actions (login required)

Edit item Edit item
Provide Feedback