A consistent metabolic hallmark observed in multiple
cancers is the increase of cellular
phosphocholine (PC) and total
choline-containing compounds (tCho), which is closely related to malignant transformation, invasion, and
metastasis.
Enzymes in
choline phospholipid metabolism present attractive targets to exploit for treatment, but require a clear understanding of the mechanisms underlying the altered
choline phospholipid metabolism observed in
cancer.
Choline kinase-α (Chk-α) is an
enzyme in the Kennedy pathway that phosphorylates free
choline (Cho) to PC, and its upregulation in several
cancers is a major contributor to increased PC levels. Similarly, increased expression and activity of
phospholipase D1 (PLD1), which converts
phosphatidylcholine (PtdCho) to
phosphatidic acid (PA) and Cho, has been well documented in gastric, ovarian and
breast cancer. Here we report a strong correlation between expression of Chk-α and PLD1 with
breast cancer malignancy. Data from patient samples established an association between
estrogen receptor (ER) status and Chk-α and PLD1 expression. In addition, these two
enzymes were found to be interactive. Downregulation of Chk-α with
siRNA increased PLD1 expression, and downregulation of PLD1 increased Chk-α expression. Simultaneous silencing of PLD1 and Chk-α in MDA-MB-231 cells increased apoptosis as detected by the TUNEL assay. These data provide new insights into
choline phospholipid metabolism of
breast cancer, and support multiple targeting of
enzymes in
choline phospholipid metabolism as a strategy for treatment.