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

British Journal of Cancer
Emily M E BarnesHector C Keun

Abstract

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. 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. 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 suffi...Continue Reading

References

Jul 4, 1990·Journal of the National Cancer Institute·P SkehanM R Boyd
Apr 1, 1993·The American Journal of Physiology·R C Poole, A P Halestrap
May 10, 2003·Pflügers Archiv : European journal of physiology·Andrew P Halestrap, David Meredith
Feb 24, 1956·Science·O WARBURG
Jun 3, 2004·Cancer Research·Rebecca L ElstromCraig B Thompson
Jul 16, 2004·Seminars in Radiation Oncology·Stefan Walenta, Wolfgang F Mueller-Klieser
Dec 3, 2008·The Journal of Biological Chemistry·Changlu LiuTimothy W Lovenberg
May 23, 2009·Science·Matthew G Vander HeidenCraig B Thompson
May 18, 2011·Analytical Biochemistry·Volker BehrendsJacob G Bundy
Sep 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Renaud Le FlochJacques Pouysségur
Mar 13, 2013·Cancer Cell·Rizwan HaqHans R Widlund
May 15, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jurre J KamphorstJoshua D Rabinowitz
Jun 26, 2013·Journal of Proteome Research·Fiona PachlBernhard Kuster
Jun 15, 2014·Cancer Research·Christina L RolandCraig D Logsdon
Mar 17, 2015·Nature Cell Biology·Lindsey K Boroughs, Ralph J DeBerardinis
Mar 18, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Thomas T VellingaOnno Kranenburg
Dec 5, 2015·Cell Cycle·Jhudit Pérez-EscuredoPierre Sonveaux
Feb 9, 2016·Cell·Christopher T HensleyRalph J DeBerardinis
Oct 19, 2016·Nature Chemical Biology·Ying-Jr ChenGary J Patti
Sep 14, 2016·Cancer Cell·Lucie BrissonPierre Sonveaux
Oct 7, 2017·Cell·Brandon FaubertRalph J DeBerardinis
Oct 19, 2017·Nature·Sheng HuiJoshua D Rabinowitz
Apr 5, 2018·Cell Metabolism·George A Brooks

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Methods Mentioned

BETA
Profiler
X-ray
Protein Assay
electrophoresis
nuclear magnetic resonance
NMR
Fluorescence

Software Mentioned

MATLAB®
GAVIN
Image
GraphPad Prism
AMDIS
Mathworks
MARS
CLARIOstar MARS

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