Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells.
Phosphoinositide 3-kinase (PI3K) is an attractive target for novel mechanism-based anticancer treatment. We used magnetic resonance (MR) spectroscopy (MRS) to detect biomarkers of PI3K signaling inhibition in human breast cancer cells. MDA-MB-231, MCF-7, and Hs578T cells were treated with the prototype PI3K inhibitor LY294002, and the (31)P MR spectra of cell extracts were monitored. In every case, LY294002 treatment was associated with a significant decrease in phosphocholine levels by up to 2-fold (P < 0.05). In addition, a significant increase in glycerophosphocholine levels by up to 5-fold was also observed (P <or= 0.05), whereas the content of glycerophosphoethanolamine, when detectable, did not change significantly. Nucleotide triphosphate levels did not change significantly in MCF-7 and MDA-MB-231 cells but decreased by approximately 1.3-fold in Hs578T cells (P = 0.01). The changes in phosphocholine and glycerophosphocholine levels seen in cell extracts were also detectable in the (31)P MR spectra of intact MDA-MB-231 cells following exposure to LY294002. When treated with another PI3K inhibitor, wortmannin, MDA-MB-231 cells also showed a significant decrease in phosphocholine content by approximately 1.25-fold relative to the control (P < 0.05), whereas the levels of the remaining metabolites did not change significantly. Our results indicate that PI3K inhibition in human breast cancer cells by LY294002 and wortmannin is associated with a decrease in phosphocholine levels.
Beloueche-Babari
Mounia
M
Cancer Research UK Clinical Magnetic Resonance Research Group, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom. Mounia.Beloueche-Babari@icr.ac.uk
Jackson
L Elizabeth
LE
Al-Saffar
Nada M S
NM
Eccles
Suzanne A
SA
Raynaud
Florence I
FI
Workman
Paul
P
Leach
Martin O
MO
Ronen
Sabrina M
SM
D000730:Androstadienes / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D002457:Cell Extracts; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005997:Glycerylphosphorylcholine / Q000032:analysis / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D009025:Morpholines / Q000494:pharmacology; D010714:Phosphatidylethanolamines / Q000032:analysis / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010767:Phosphorylcholine / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D002457:Cell Extracts; D002867:Chromones; D004791:Enzyme Inhibitors; D005997:Glycerylphosphorylcholine; D009025:Morpholines; D010714:Phosphatidylethanolamines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010767:Phosphorylcholine; D000077191:Wortmannin; C002449:glycerophosphoethanolamine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one