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Mori, Noriko; Wildes, Flonné; Kakkad, Samata; Jacob, Desmond; Solaiyappan, Meiyappan; Glunde, Kristine; Bhujwalla, Zaver M.
NMR in biomedicine, December 2015, Volume: 28, Issue: 12Journal Article
High levels of total choline and phosphocholine (PC) are consistently observed in aggressive cancers. Choline kinase (Chk) catalyzes choline phosphorylation to produce PC in phosphatidylcholine (PtdCho) biosynthesis. PtdCho is the most abundant phospholipid in eukaryotic cell membranes and plays a dual role as the structural component of membranes and as a substrate to produce lipid second messengers such as phosphatidic acid and diacylglycerol. Chk‐α, but not Chk‐β, is overexpressed in various cancers, and is closely associated with tumor progression and invasiveness. We have previously shown that downregulation of mRNA using small interfering RNA (siRNA) against Chk‐α (siRNA‐Chk) or Chk short hairpin RNA, and the resultant decrease of Chk‐α protein levels, significantly reduced proliferation in breast cancer cells and tumors. A novel potent and selective small‐molecule Chk‐α inhibitor, V‐11‐0711, that inhibits the catalytic activity of Chk has recently been developed. Here, we used triple negative MDA‐MB‐231 and SUM149 breast cancer cells to further investigate the role of Chk‐α in cancer, by examining Chk‐α protein levels, cell viability/proliferation, choline phospholipid and lipid metabolism, lipid droplet formation, and apoptosis, following treatment with V‐11‐0711. Under the conditions used in this study, treatment with V‐11‐0711 significantly decreased PC levels but did not reduce cell viability as long as Chk‐α protein and PtdCho levels were not reduced, suggesting that Chk‐α protein and PtdCho, but not PC, may be crucial for breast cancer cell survival. These data also support the approach of antitumor strategies that destabilize Chk‐α protein or downregulate PtdCho in breast cancer treatment. Copyright © 2015 John Wiley & Sons, Ltd. Here, we have used triple negative breast cancer cell lines, MDA‐MB‐231 and SUM149, to investigate the role of choline kinase‐α (Chk‐α) by examination of Chk‐α protein level, cell viability, choline phospholipid and lipid metabolism, lipid droplet formation, and apoptosis, following treatment with a novel selective Chk‐α inhibitor, V‐11‐0711, which inhibits the catalytic activity of Chk‐α. Under the conditions used our results demonstrate that a low phosphocholine (PC) level does not reduce cell viability if the Chk‐α protein level and phosphatidylcholine (PtdCho) level are not reduced, suggesting that Chk‐α protein (not catalytic activity) and PtdCho, but not PC, may be crucial for breast cancer cell survival and proliferation. These data support the approach of antitumor strategies that destabilize Chk‐α protein or downregulate PtdCho level in breast cancer.
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