The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth
| Autor: | Trousil, Sebastian, Kaliszczak, Maciej, Schug, Zachary, Nguyen, Quang-De, Tomasi, Giampaolo, Favicchio, Rosy, Brickute, Diana, Fortt, Robin, Twyman, Frazer J., Carroll, Laurence, Kalusa, Andrew, Navaratnam, Naveenan, Adejumo, Thomas, Carling, David, Gottlieb, Eyal, Aboagye, Eric O. |
|---|---|
| Přispěvatelé: | Cancer Research UK |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Science & Technology
positron emission tomography choline kinase MALIGNANT-TRANSFORMATION PROLIFERATION Cell Biology MAGNETIC-RESONANCE-SPECTROSCOPY MAMMARY EPITHELIAL-CELLS PROSTATE-CANCER ALPHA PHOSPHOLIPID-METABOLISM POSITRON-EMISSION-TOMOGRAPHY Oncology mitochondrial function PHOSPHATIDYLCHOLINE cancer BREAST-CANCER Life Sciences & Biomedicine metabolism |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|