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BMC Cancer. 2018 Jun 26;18(1):689. doi: 10.1186/s12885-018-4599-8.

Benzylserine inhibits breast cancer cell growth by disrupting intracellular amino acid homeostasis and triggering amino acid response pathways.

Author information

1
Origins of Cancer Program, Centenary Institute, University of Sydney, Locked Bag 6, Newtown, NSW, 2042, Australia.
2
Sydney Medical School, University of Sydney, Sydney, Australia.
3
School of Mathematics and Statistics, University of Sydney, Sydney, Australia.
4
School of Medical Sciences, University of New South Wales, Sydney, Australia.
5
Transporter Biology Group, Discipline of Pharmacology, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
6
School of Life and Environmental Sciences, University of Sydney, Sydney, Australia.
7
Charles Perkins Centre, University of Sydney, Sydney, Australia.
8
Origins of Cancer Program, Centenary Institute, University of Sydney, Locked Bag 6, Newtown, NSW, 2042, Australia. j.holst@centenary.org.au.
9
Sydney Medical School, University of Sydney, Sydney, Australia. j.holst@centenary.org.au.

Abstract

BACKGROUND:

Cancer cells require increased levels of nutrients such as amino acids to sustain their rapid growth. In particular, leucine and glutamine have been shown to be important for growth and proliferation of some breast cancers, and therefore targeting the primary cell-surface transporters that mediate their uptake, L-type amino acid transporter 1 (LAT1) and alanine, serine, cysteine-preferring transporter 2 (ASCT2), is a potential therapeutic strategy.

METHODS:

The ASCT2 inhibitor, benzylserine (BenSer), is also able to block LAT1 activity, thus inhibiting both leucine and glutamine uptake. We therefore aimed to investigate the effects of BenSer in breast cancer cell lines to determine whether combined LAT1 and ASCT2 inhibition could inhibit cell growth and proliferation.

RESULTS:

BenSer treatment significantly inhibited both leucine and glutamine uptake in MCF-7, HCC1806 and MDA-MB-231 breast cancer cells, causing decreased cell viability and cell cycle progression. These effects were not primarily leucine-mediated, as BenSer was more cytostatic than the LAT family inhibitor, BCH. Oocyte uptake assays with ectopically expressed amino acid transporters identified four additional targets of BenSer, and gas chromatography-mass spectrometry (GCMS) analysis of intracellular amino acid concentrations revealed that this BenSer-mediated inhibition of amino acid uptake was sufficient to disrupt multiple pathways of amino acid metabolism, causing reduced lactate production and activation of an amino acid response (AAR) through activating transcription factor 4 (ATF4).

CONCLUSIONS:

Together these data showed that BenSer blockade inhibited breast cancer cell growth and viability through disruption of intracellular amino acid homeostasis and inhibition of downstream metabolic and growth pathways.

KEYWORDS:

Amino acids; Luminal A; Metabolism; Stress response; Triple-negative

PMID:
29940911
PMCID:
PMC6019833
DOI:
10.1186/s12885-018-4599-8
[Indexed for MEDLINE]
Free PMC Article

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