Choline kinase-α protein and phosphatidylcholine but not phosphocholine are required for breast cancer cell survival.
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.
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Noriko
N
Mori
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Flonné
F
Wildes
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Samata
S
Kakkad
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Desmond
D
Jacob
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Meiyappan
M
Solaiyappan
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.|Sidney Kimmel Comprehensive Cancer Center, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Kristine
K
Glunde
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.|Sidney Kimmel Comprehensive Cancer Center, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.
Zaver M
ZM
Bhujwalla
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002797:Choline Kinase / Q000378:metabolism*; D006801:Humans; D010713:Phosphatidylcholines / Q000378:metabolism*; D010767:Phosphorylcholine / Q000378:metabolism*; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods
D010713:Phosphatidylcholines; D010767:Phosphorylcholine; C517212:CHKA protein, human; D002797:Choline Kinase
MRS; breast cancer; choline kinase; lipid droplets; lipid metabolism; phosphatidylcholine; phosphocholine