TY - JOUR
T1 - Targeted AKT inhibition in prostate cancer cells and spheroids reduces aerobic glycolysis and generation of hyperpolarized [1-13C] lactate
AU - Tee, Sui Seng
AU - Suster, Izabela
AU - Truong, Steven
AU - Jeong, Sangmoo
AU - Eskandari, Roozbeh
AU - DiGialleonardo, Valentina
AU - Alvarez, Julio A.
AU - Aldeborgh, Hannah N.
AU - Keshari, Kayvan R.
N1 - Funding Information:
This research was funded in part through the NIH/NCI Cancer Center Support grant P30 CA008748 (to K.R. Keshari), NIH/NCI R01 CA195476 and NIH/NIBIB R00 EB014328 (to K.R. Keshari) as well as Memorial Sloan Kettering's Center for Molecular Imaging and Nanotechnology (CMINT; to S.S. Tee).
Publisher Copyright:
© 2018 AACR.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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 NADp/ 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.
AB - 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 NADp/ 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.
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U2 - 10.1158/1541-7786.MCR-17-0458
DO - 10.1158/1541-7786.MCR-17-0458
M3 - Article
C2 - 29330287
AN - SCOPUS:85045376040
SN - 1541-7786
VL - 16
SP - 453
EP - 460
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
IS - 3
ER -
