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Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells

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Title: Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells
Authors: Barnes, EME
Xu, Y
Benito, A
Herendi, L
Siskos, AP
Aboagye, EO
Keun, H
Nijhuis, A
Item Type: Journal Article
Abstract: Background Akt signalling regulates glycolysis and drives the Warburg effect in cancer, thus decreased glucose utilisation is a pharmacodynamic marker of Akt inhibition. However, cancer cells can utilise alternative nutrients to glucose for energy such as lactate, which is often elevated in tumours together with increased acidity. We therefore hypothesised that lactic acidosis may confer resistance to Akt inhibition. Methods The effect of the pan-Akt inhibitor uprosertib (GSK2141795), on HCT116 and LS174T colon cancer cells was evaluated in the presence and absence of lactic acid in vitro. Expression of downstream Akt signalling proteins was determined using a phosphokinase array and immunoblotting. Metabolism was assessed using 1H nuclear magnetic resonance spectroscopy, stable isotope labelling and gas chromatography-mass spectrometry. Results Lactic acid-induced resistance to uprosertib was characterised by increased cell survival and reduced apoptosis. Uprosertib treatment reduced Akt signalling and glucose uptake irrespective of lactic acid supplementation. However, incorporation of lactate carbon and enhanced respiration was maintained in the presence of uprosertib and lactic acid. Inhibiting lactate transport or oxidative phosphorylation was sufficient to potentiate apoptosis in the presence of uprosertib. Conclusions Lactic acidosis confers resistance to uprosertib, which can be reversed by inhibiting lactate transport or oxidative metabolism.
Issue Date: 10-Mar-2020
Date of Acceptance: 30-Jan-2020
URI: http://hdl.handle.net/10044/1/78766
DOI: 10.1038/s41416-020-0777-y
ISSN: 0007-0920
Publisher: Springer Nature [academic journals on nature.com]
Start Page: 1298
End Page: 1308
Journal / Book Title: British Journal of Cancer
Volume: 122
Copyright Statement: © 2020 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
Sponsor/Funder: Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Cancer Research UK
Funder's Grant Number: 19482
RDB01
MR/N020782/1
16584
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
LACTATE METABOLISM
RESPIRATION
GSK2141795
METFORMIN
SURVIVAL
FAMILY
GROWTH
MCT1
1112 Oncology and Carcinogenesis
1117 Public Health and Health Services
Oncology & Carcinogenesis
Publication Status: Published
Online Publication Date: 2020-03-10
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine