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Mol Cancer Res. 2018 Mar;16(3):453-460. doi: 10.1158/1541-7786.MCR-17-0458. Epub 2018 Jan 12.

Targeted AKT Inhibition in Prostate Cancer Cells and Spheroids Reduces Aerobic Glycolysis and Generation of Hyperpolarized [1-13C] Lactate.

Author information

1
Department of Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Hunter College, New York, New York.
3
Weill Cornell Medical College, New York, New York.
4
Department of Radiology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York. rahimikk@mskcc.org.

Abstract

The PI3K/AKT/mTOR (PAM) signaling pathway is frequently mutated in prostate cancer. Specific AKT inhibitors are now in advanced clinical trials, and this study investigates the effect of MK2206, a non-ATP-competitive inhibitor, on the cellular metabolism of prostate cancer cells. We observed a reduction in cell motility and aerobic glycolysis in prostate cancer cells with treatment. These changes were not accompanied by a reduction in the ratio of high-energy phosphates or a change in total protein levels of enzymes and transporters involved in glycolysis. However, a decreased ratio of NAD+/NADH was observed, motivating the use of hyperpolarized magnetic resonance spectroscopy (HP-MRS) to detect treatment response. Spectroscopic experiments were performed on tumor spheroids, 3D structures that self-organize in the presence of an extracellular matrix. Treated spheroids showed decreased lactate production with on-target inhibition confirmed using IHC, demonstrating that HP-MRS can be used to probe treatment response in prostate cancer spheroids and can provide a biomarker for treatment response. Mol Cancer Res; 16(3); 453-60. ©2018 AACR.

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