The
glycerophospholipid phosphatidylcholine is the most abundant
phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for
cancer cell growth. Inhibition of
choline kinase alpha (CHKA), the first committed step to
phosphatidylcholine synthesis, by the selective small-molecule
ICL-CCIC-0019, potently suppressed growth of a panel of 60
cancer cell lines with median GI50 of 1.12 μM and inhibited
tumor xenograft growth in mice.
ICL-CCIC-0019 decreased
phosphocholine levels and the fraction of labeled
choline in
lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in
phosphocholine cellular levels following treatment could be detected non-invasively in
tumor xenografts by [18F]-fluoromethyl-[1,2-2H4]-
choline positron emission tomography. Herein, we reveal a previously unappreciated effect of
choline metabolism on mitochondria function. Comparative metabolomics demonstrated that
phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without
reactive oxygen species activation.
Drug treatment decreased mitochondria function with associated reduction of
citrate synthase expression and AMPK activation.
Glucose and
acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that
choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of
phospholipids.