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

Palanivel Kandasamy,Senji Shirasawa,Jonai Pujol‐Giménez,Damian T Nydegger,Matthias A Hediger,Inti Zlobec,Toshiyuki Tsunoda,Rajesh Bhardwaj

doi:10.1002/1878-0261.12999

Palanivel Kandasamy, Senji Shirasawa + Show 6 more

Open Access

https://doi.org/10.1002/1878-0261.12999

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Journal: Molecular oncology	Publication Date: Jun 18, 2021
Citations: 21	License type: CC BY 4.0

Affiliation: University of Bern, Fukuoka University

Abstract

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.

Highlights

Tumor cells take up high amounts of amino acids (AAs) from the extracellular milieu in order to sustain proliferation and metastasis
To evaluate whether the observed increase in L-glutamine uptake by kirsten rat sarcoma (KRAS) mutant colorectal cancer (CRC) cells correlate with general increase in the uptake of essential amino acid (EAA), we measured L-leucine uptake in the same CRC cell line panel
To examine whether the increased glutamine uptake is linked to increased proliferation of KRAS mutant CRC cells, cells were grown in medium containing different concentrations of glutamine (0.5–5 mM) for 5 days

Summary

Introduction

Tumor cells take up high amounts of amino acids (AAs) from the extracellular milieu in order to sustain proliferation and metastasis. Tumor cells upregulate certain AATs in order to facilitate the transport of AAs into and out of cells. Recent reports revealed that cancer cells exhibit alterations in expression and/or function of specific AATs in order to take up exogenous AAs depending on the specific requirement of the tumor subtypes [1,2]. Glutamine is a conditionally essential amino acid (EAA) that contributes even at relatively low concentrations toward proliferation of normal healthy cells. Tumor cells require much higher levels of glutamine to survive [6]

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