TGF[beta]1-induced leucine limitation uncovered by differential ribosome codon reading

Cancer cells modulate their metabolic networks to support cell proliferation and a higher demand of building blocks. These changes may restrict the availability of certain amino acids for protein synthesis, which can be utilized for cancer therapy. However, little is known about the amino acid deman...

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Bibliographic Details
Published in:EMBO reports 2017-04, Vol.18 (4), p.549
Main Authors: Loayza-Puch, Fabricio, Rooijers, Koos, Zijlstra, Jelle, Moumbeini, Behzad, Zaal, Esther A, Oude Vrielink, Joachim F, Lopes, Rui, Ugalde, Alejandro P, Berkers, Celia R, Agami, Reuven
Format: Article
Language:English
Subjects:
Amino acids
Cancer
Cell growth
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Summary:Cancer cells modulate their metabolic networks to support cell proliferation and a higher demand of building blocks. These changes may restrict the availability of certain amino acids for protein synthesis, which can be utilized for cancer therapy. However, little is known about the amino acid demand changes occurring during aggressive and invasive stages of cancer. Recently, we developed diricore, an approach based on ribosome profiling that can uncover amino acid limitations. Here, we applied diricore to a cellular model in which epithelial breast cells respond rapidly to TGF[beta]1, a cytokine essential for cancer progression and metastasis, and uncovered shortage of leucine. Further analyses indicated that TGF[beta]1 treatment of human breast epithelial cells reduces the expression of SLC3A2, a subunit of the leucine transporter, which diminishes leucine uptake and inhibits cell proliferation. Thus, we identified a specific amino acid limitation associated with the TGF[beta]1 response, a vulnerability that might be associated with aggressiveness in cancer. Synopsis TGF[beta]1 treatment of human breast epithelial cells reduces the expression of SLC3A2, a subunit of the leucine transporter, which diminishes leucine uptake and inhibits cell proliferation. TGF[beta]1 induces pausing of ribosomes at leucine codons in MCF10A cells. MCF10A cells downregulate the leucine transporter SLC3A2 and reduce leucine uptake in response to TGF[beta]1. Exogenous leucine releases the codon-specific stalling induced by TGF[beta]1. Reconstitution of the SLC3A2 transporter rescues the stalling of ribosomes at leucine codons as well as TGF[beta]1-induced proliferation inhibition.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.201744000