Changes in choline metabolism as potential biomarkers of phospholipase C{gamma}1 inhibition in human prostate cancer cells.
Phosphoinositide-specific phospholipase Cγ1 (PLCγ1) is activated downstream of many receptor tyrosine kinases to promote cell motility. Inhibition of this protein is being explored as a therapeutic strategy for blocking cancer cell invasion and metastasis. The clinical development of such cytostatic therapies requires the implementation of pharmacodynamic biomarkers of target modulation. In this study, we use magnetic resonance spectroscopy to explore metabolic biomarkers of PLCγ1 down-regulation in PC3LN3 prostate cancer cells. We show that inhibition of PLCγ1 via an inducible short hairpin RNA system causes a reduction in phosphocholine levels by up to 50% relative to the control as detected by (1)H and (31)P magnetic resonance spectroscopy analyses. This correlated with a rounded-up morphology and reduced cell migration. Interestingly, the fall in phosphocholine levels was not recorded in cells with constitutive PLCγ1 knockdown where the rounded-up phenotype was no longer apparent. This study reveals alterations in metabolism that accompany the cellular effects of PLCγ1 knockdown and highlights phosphocholine as a potential pharmacodynamic biomarker for monitoring the action of inhibitors targeting PLCγ1 signaling.
Cancer Research UK Clinical Magnetic Resonance Research Group, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. Mounia.Beloueche-Babari@icr.ac.uk
Mounia
M
Beloueche-Babari
Joanna C
JC
Peak
L Elizabeth
LE
Jackson
May-Yung
MY
Tiet
Martin O
MO
Leach
Suzanne A
SA
Eccles
D000818:Animals; D014408:Biomarkers, Tumor; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D010767:Phosphorylcholine / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference
D014408:Biomarkers, Tumor; D010767:Phosphorylcholine; D051966:Phospholipase C gamma